Self-pressurized capsule for drug delivery

Abstract

A dosage form for administration of a drug to a patient is provided. The dosage form includes a capsule comprising a capsule wall defining an interior space; drug particles disposed within the interior space adjacent a pre-defined area of weakness in the capsule; and an excipient composition located within the interior space, wherein the excipient composition is configured to react, or to phase change, and produce a gas which pressurizes the interior space and ruptures the pre-defined area of weakness in the capsule to form a release aperture in the capsule through which the drug particles are ejected together with the gas. The dosage form may be configured to deliver the drug particles to any mucosal surface in the patient. For example, the dosage form may be an oral dosage form configured to release the drug particles and penetrate a mucosal barrier within the gastrointestinal tract.

Description

SELF-PRESSURIZED CAPSULE FOR DRUG DELIVERYCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 554,672, filed February 16, 2024, which is incorporated herein by reference.BACKGROUND

[0002] Therapeutics, including biologic therapeutics, as well as non-biologic drugs, play a critical role in the management of chronic diseases and may significantly improve patient quality of life. Patients often receive therapeutics for chronic diseases for their entire lifetime, but the most common routes of biologies administration are intravenous infusion or subcutaneous injection, both of which have several disadvantages. Injections are an invasive form of administration that generates sharps waste, that sometimes requires trained professionals, and that may be painful, which may result in needle phobia and lower patient adherence.

[0003] Oral administration offers several potential advantages over injections, but the gastrointestinal tract (GIT) presents delivery challenges that can severely limit the oral bioavailability of biologies and non-biologic drugs. Taken orally, biologies have very poor bioavailability, mostly due to the physiological and protective properties of the GIT. These properties include four major barriers that biologies must overcome for therapeutic efficacy when delivered orally: a chemical barrier (fluctuations of pH from highly acidic in the stomach to slightly basic in the colon), an enzymatic barrier (94-98% orally administered proteins are digested by enzymes in the GIT), and two physical barriers: the epithelial cell layer (ECL) and the thick mucus barrier (MB) covering the ECL.

[0004] Many methods for oral delivery7of biologies have been proposed and investigated, which are passive and rely on diffusion across the MB and ECL as the main mechanism of transport. These conventional methods may have limited success in traversing the barriers and have led to researchers needing to combine other materials and methods to achieve drug administration, such as chemical modification of the biologies, and / or the addition of permeation enhancers and enzy me inhibitors to the drug formulations.

[0005] Efforts have been made to shift from passive methods of traversing the mucosal barrier with the oral biologic to more active methods, such as those in which delivery' of the biologic involves application of force. For example, the MucoJet™, which is a microelectromechanical systems-based drug delivery' technology7, and the BioJet™ function like liquid jet injectors, the RoboCap uses a tiny motor and rotating turbine fins to locally clearaway the MB, while other capsules (SOMA, LUMI. RaniPill) work by injecting drug-loaded miconeedles or millimeter-sized needles through the MB and ECL. However, all of these capsules have complex designs that would be difficult to manufacture on a large scale with existing technology at a low cost.

[0006] Accordingly, it would be desirable to provide alternative means for delivery of biologies and other drugs across the GIT physical barriers, preferably with simpler and more cost-effective dosage forms, particular oral dosage forms that can enhance delivery and uptake of biologic drugs through intestinal tissues.SUMMARY

[0007] In one aspect, a dosage form for administration of a drug to a patient is provided. The dosage form includes: a capsule comprising a capsule wall defining an interior space; drug particles disposed within a first portion of the interior space adjacent a pre-defined area of weakness in the capsule; and an excipient composition located within the interior space, wherein the excipient composition is configured to react, or to phase change, and produce a gas which pressurizes the interior space. The pre-defined area of weakness in the capsule is configured to rupture under the pressurization by the gas. forming a release aperture through the capsule (capsule wall and / or a coating thereon) through which the drug particles are ejected together with the gas.

[0008] In another aspect, a method of administering a drug to a patient is provided. The method includes: (i) administering, e.g.. orally, a dosage form into the patient, wherein the dosage form includes a capsule defining an interior space; drug particles disposed within a first portion of the interior space adjacent a pre-defined area of weakness in the capsule; and an excipient composition located within the interior space, wherein the excipient composition is configured to react, or to phase change, in vivo and produce a gas which pressurizes the interior space; and then (ii) ejecting the drug particles from the capsule toward a mucosal barrier, e.g., in the gastrointestinal tract, within the patient upon generation of a pressure within the dosage form sufficient to rupture the pre-defined area of weakness in the capsule of the dosage form.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] The detailed description is set forth with reference to the accompanying drawings. The use of the same reference numerals may indicate similar or identical items. Various embodiments may utilize elements and / or components other than those illustrated in the drawings, and some elements and / or components may not be present in various embodiments. Elements and / or components are not necessarily drawn to scale.

[0010] FIG. 1 is a perspective view of a self-pressurized oral dosage form, according to one or more embodiments of the present disclosure.

[0011] FIG. 2A is an exploded view of the self-pressurized oral dosage form of FIG. 1, according to one or more embodiments of the present disclosure.

[0012] FIG. 2B is a partially assembled exploded view of the self-pressurized oral dosage form of FIG. 1, according to one or more embodiments of the present disclosure.

[0013] FIG. 2C is a cross-sectional view of the self-pressurized oral dosage form of FIG. 1, according to one or more embodiments of the present disclosure.

[0014] FIG. 3 is an interior cutaway, partial cross-sectional view of the self-pressurized oral dosage form of FIG. 1, according to one or more embodiments of the present disclosure.

[0015] FIG. 4A is an exploded view of the drug-containing portion of the oral dosage form of FIG. 3, according to one or more embodiments of the present disclosure.

[0016] FIG. 4B is an assembled view of the drug-containing portion of FIG. 4A, according to one or more embodiments of the present disclosure.

[0017] FIGS. 5A-5C are interior cross-sectional views of excipient chambers within the oral dosage form of FIG. 3, according to one or more embodiments of the present disclosure.

[0018] FIGS. 6A-6D are cross-sectional views of the pre-defined area of weakness of the oral dosage form of FIG. 3, according to one or more embodiments of the present disclosure.

[0019] FIG. 7 depicts a process of releasing a drug from a self-pressurized oral dosage form, according to one or more embodiments of the present disclosure.

[0020] FIG. 8 depicts the delivery of nanoparticles to intestinal mucosa via pressurized delivery means, according to one or more embodiments of the present disclosure.

[0021] FIGS. 9A-9F are graphs of nanoparticle distribution after ex vivo pressurized delivery, according to one or more embodiments of the present disclosure.

[0022] FIGS. 10A-10B are graphs of the percentage of nanoparticles reaching various distance ranges from the epithelial cell layer of intestinal mucosa following pressurized delivery', according to one or more embodiments of the present disclosure.

[0023] FIGS. 11 A-l 1C are brightfield microscopy images after pressurized delivery of insulin and nanoparticles to intestinal mucosa, according to one or more embodiments of the present disclosure.

[0024] FIGS. 12A-12C are brightfield microscopy images of intestinal mucosa after passive delivery of insulin and nanoparticles, according to one or more embodiments of the present disclosure.

[0025] FIGS. 12D-12F are brightfield microscopy images after pressurized delivery' of insulin and nanoparticles to intestinal mucosa, according to one or more embodiments of the present disclosure.

[0026] FIGS. 13A-13F are brightfield microscopy images of successive small intestinal tissue sections after pressurized delivery of insulin and nanoparticles, according to one or more embodiments of the present disclosure.

[0027] FIGS. 13G-13L are brightfield microscopy images of successive small intestinal tissue sections after passive delivery of insulin and nanoparticles, according to one or more embodiments of the present disclosure.

[0028] FIG. 13M is a brightfield microscopy image of untreated small intestinal tissue, according to one or more embodiments of the present disclosure.

[0029] FIG. 14A is a graph of experimentally fitted values for water permeance through exemplary coated gelatin capsules after UV irradiation, according to one or more embodiments of the present disclosure.

[0030] FIG. 14B is a graph of model-derived elastic modulus values of coated gelatin capsules after UV irradiation, according to one or more embodiments of the present disclosure.

[0031] FIG. 14C is a graph of model-derived delivery pressure, according to one or more embodiments of the present disclosure.

[0032] FIG. 14D is a graph of model-derived delivery time, according to one or more embodiments of the present disclosure.

[0033] FIGS. 15A-15D are graphs of the effects of gelatin treatment on stability, according to one or more embodiments of the present disclosure.

[0034] FIG. 15E is a graph of the effect of delivery orifice size on capsule delivery pressure, according to one or more embodiments of the present disclosure.

[0035] FIG. 15F is a graph of the effect of UV irradiation time on capsule delivery pressure, according to one or more embodiments of the present disclosure.

[0036] FIGS. 16A-16B are graphs of the effect of delivery' orifice size on delivery' pressure, according to one or more embodiments of the present disclosure.

[0037] FIGS. 16C-16D are graphs of the effect of delivery orifice size on time until delivery, according to one or more embodiments of the present disclosure.

[0038] FIG. 16E is a graph of the effect of capsule crosslinking on capsule pressure, according to one or more embodiments of the present disclosure.

[0039] FIG. 17A is a graph of the delivery distance as a function of time for various capsules, according to one or more embodiments of the present disclosure.

[0040] FIG. 17B is a graph of delivery velocity as a function of time for various capsules, according to one or more embodiments of the present disclosure.

[0041] FIG. 17C is a plot of delivery' velocity as a function of delivery orifice size, according to one or more embodiments of the present disclosure.

[0042] FIGS. 18A-18E are graphs of the average blood glucose level change from baseline over time following pressurized delivery’ of insulin, according to one or more embodiments of the present disclosure.

[0043] FIG. 18F is a graphical representation of the average human insulin concentration in plasma over time, according to one or more embodiments of the present disclosure.

[0044] FIG. 18G is a plot of the area under the curve for each of FIGS. 18A-18E, according to one or more embodiments of the present disclosure.

[0045] FIG. 19 is a graph of the pressure for a capsule having coated citric acid and uncoated sodium bicarbonate, according to one or more embodiments of the present disclosure.

[0046] FIG. 20 is a graph of the pressure for a capsule having coated sodium bicarbonate and uncoated citric acid, according to one or more embodiments of the present disclosure.

[0047] FIGS. 21A-21B are graphs of the capsule pressure for capsules coated with PVP. according to one or more embodiments of the present disclosure.

[0048] FIG. 22A is a graph of capsule pressure as a function of time for enteric-coated and non-enteric coated capsules in different gastrointestinal fluids, according to one or more embodiments of the present disclosure.

[0049] FIG. 22B is a graph of capsule burst pressure for enteric-coated and non-enteric coated capsules in different gastrointestinal fluids, according to one or more embodiments of the present disclosure.

[0050] FIG. 22C is a graph of capsule pressurization rate for enteric-coated and non-enteric coated capsules in different gastrointestinal fluids, according to one or more embodiments of the present disclosure.

[0051] FIG. 22D is a graph of the time to burst for enteric-coated and non-enteric coated capsules in different gastrointestinal fluids, according to one or more embodiments of the present disclosure.

[0052] FIGS. 23A-23C are graphs of comparing water uptake of capsules having different coatings, according to one or more embodiments of the present disclosure.

[0053] FIG. 24 is a graph of the pressure over time for a capsule containing only sodium bicarbonate, according to one or more embodiments of the present disclosure.

[0054] FIG. 25 is a graph comparing the effect of Eudragit coatings on capsule pressure, according to one or more embodiments of the present disclosure.

[0055] FIG. 26A is a graph comparing the burst pressure, pressurization rate, and time to burst as a function of enteric coating thickness, according to one or more embodiments of the present disclosure.

[0056] FIG. 26B is a graph comparing the burst pressure, pressurization rate, and time to burst as a function of time in SGF. according to one or more embodiments of the present disclosure.

[0057] FIGS. 27A-27B are graphs of the effect of capsule coating on water uptake, according to one or more embodiments of the present disclosure.

[0058] FIG. 28 is a graph of capsule pressure as a function of time for enteric coated capsules in SGF, according to one or more embodiments of the present disclosure.

[0059] FIG. 29A is a graph of burst pressure for newly prepared and stored capsules, according to one or more embodiments of the present disclosure.

[0060] FIG. 29B is a graph of pressurization rate for newly prepared and stored capsules, according to one or more embodiments of the present disclosure.

[0061] FIG. 29C is a graph of time to burst for newly prepared and stored capsules, according to one or more embodiments of the present disclosure.

[0062] FIG. 29D is a graph of water content for newly prepared and stored capsules, according to one or more embodiments of the present disclosure.

[0063] FIG. 30A is a graph of pressure over time for a capsule filled with effervescent excipients, according to one or more embodiments of the present disclosure.

[0064] FIG. 30B is a graph of pressure over time for effervescent excipients removed from a capsule, according to one or more embodiments of the present disclosure.

[0065] FIG. 31 A is a graph comparing the burst pressure for capsules with and without desiccant, according to one or more embodiments of the present disclosure.

[0066] FIG. 3 IB is a graph comparing the time to burst for capsules with and without desiccant, according to one or more embodiments of the present disclosure.

[0067] FIG. 32A is a graph comparing burst pressure for capsules with pre-dried and nondried effervescent excipients, according to one or more embodiments of the present disclosure.

[0068] FIG. 32B is a graph comparing the time to burst for capsules with pre-dried and non-dried effervescent excipients, according to one or more embodiments of the present disclosure.

[0069] FIG. 33A is a graph comparing the effect of capsule coating on water uptake for capsules with effervescent excipients, according to one or more embodiments of the present disclosure.

[0070] FIG. 33B is a graph comparing the effect of capsule coating on water uptake for capsules without effervescent excipients, according to one or more embodiments of the present disclosure.

[0071] FIG. 34A is a graph comparing burst pressure, pressurization rate, and time to burst for non-enteric-coated capsules with non-dried and dried excipients, according to one or more embodiments of the present disclosure.

[0072] FIG. 34B-34C graph comparing water uptake for non-enteric-coated (FIG. 34B) and enteric-coated capsules (FIG. 34C), according to one or more embodiments of the present disclosure.

[0073] FIG. 34D is a graph comparing burst pressure, pressurization rate, and time to burst for non-enteric coated capsules with dried excipients, according to one or more embodiments of the present disclosure.

[0074] FIG. 34E is a graph companng burst pressure, pressurization rate, and time to burst for enteric-coated capsules with dried excipients, according to one or more embodiments of the present disclosure.

[0075] FIG. 35A is a graph comparing water uptake for capsules without excipients incubated in Simulated Intestinal Fluid (SIF) or Simulated Gastric Fluid (SGF), according to one or more embodiments of the present disclosure.

[0076] FIG. 35B is a graph comparing water uptake for capsules with non-effervescent excipients incubated in SIF or SGF, according to one or more embodiments of the present disclosure.

[0077] FIG. 35C is a graph comparing water uptake for capsules with and without non- effervescent excipients incubated in SIF or SGF, according to one or more embodiments of the present disclosure.

[0078] FIG. 36A is a graph of capsule pressure as a function of time for enteric-coated and non-enteric-coated capsules in gastrointestinal fluid, according to one or more embodiments of the present disclosure.

[0079] FIG. 36B is a graph of burst pressure for enteric-coated and non-enteric-coated capsules in gastrointestinal fluid, according to one or more embodiments of the present disclosure.

[0080] FIG. 36C is a graph of pressurization rate for enteric-coated and non-enteric-coated capsules in gastrointestinal fluid, according to one or more embodiments of the present disclosure.

[0081] FIG. 36D is a graph of time to burst for enteric-coated and non-enteric-coated capsules in gastrointestinal fluid, according to one or more embodiments of the present disclosure.

[0082] FIG. 37A is a graph comparing capsule burst pressure before and after 3-night storage, according to one or more embodiments of the present disclosure.

[0083] FIG. 37B is a graph comparing capsule time to burst before and after 3-night storage, according to one or more embodiments of the present disclosure.

[0084] FIG. 38A is a graph of burst pressure for capsules before and after storage, followed by testing in SIF, according to one or more embodiments of the present disclosure.

[0085] FIG. 38B is a graph of pressurization rate capsules before and after storage, followed by testing in SIF, according to one or more embodiments of the present disclosure.

[0086] FIG. 38C is a graph of time to burst for capsules before and after storage, followed by testing in SIF. according to one or more embodiments of the present disclosure.

[0087] FIG. 39A is a graph of burst pressure, pressurization rate, and time to burst for non- enteric-coated capsules stored at low humidity with dried excipients, according to one or more embodiments of the present disclosure.

[0088] FIG. 39B is a graph of water content for non-enteric-coated capsules stored at low humidity, according to one or more embodiments of the present disclosure.

[0089] FIG. 39C is a graph of burst pressure, pressurization rate, and time to burst for enteric-coated capsules stored at low humidity with dried excipients, according to one or more embodiments of the present disclosure.

[0090] FIG. 39D is a graph of burst pressure, pressurization rate, and time to burst for non- enteric-coated capsules with non-dried excipient stored at low humidity, according to one or more embodiments of the present disclosure.

[0091] FIG. 40A is a graph of burst pressure over time in storage for non-enteric-coated capsules with dried excipients stored at low humidity, according to one or more embodiments of the present disclosure.

[0092] FIG. 40B is a graph of pressurization rate over time in storage for non-enteric- coated capsules with dried excipients stored at low' humidity, according to one or more embodiments of the present disclosure.

[0093] FIG. 40C is a graph of time to burst over time in storage for non-enteric-coated capsules with dried excipients stored at low humidity, according to one or more embodiments of the present disclosure.

[0094] FIG. 41 A is a graph of capsule failure rate under differing storage conditions with desiccant (+D) or without desiccant (-D), according to one or more embodiments of the present disclosure.

[0095] FIGS. 41B-41C are graphs of capsule pressure as a function of time for fumaric acid and sodium bicarbonate excipients and 0.13 %w / w PVP-coated excipients, respectively, according to one or more embodiments of the present disclosure.DETAILED DESCRIPTION

[0096] Drug delivery' dosage forms have been developed which are configured to eject drug particles in vivo at velocities effective to penetrate one or more barriers to uptake of the drug by the body of a patient, such as the mucosal barrier in the gastrointestinal tract. In a particularly advantageous embodiment, the dosage form is an oral dosage form including a capsule designed to protect the drug from degradation in the stomach and then facilitate release of the drug to the small intestine for systemic uptake. This functionality is particularly useful for biologies, although any suitable drug may be administered with the presently disclosed dosage form.

[0097] The term “mucosal barrier” includes mult pie barriers: the non-adherent mucus, the adherent mucus, the non-adherent + adherent mucus (i. e. , “the mucus”), and the epithelial cell layer. The gas and drug particles ejected from the dosage form may push the mucus away, and / or may drive the drug particles through / across the mucus and / or through / across the epithelial cell layer.

[0098] The dosage form advantageously may be self-administrable, does not generate sharps waste, and is based on a relatively simple capsule design to facilitate large scale, cost- effective manufacture, since the dosage form does not include springs, needles, motors, or any electromechanical components. In addition, the pressurized delivery of the drug particles from the present dosage form may facilitate a significantly faster delivery as compared to a conventional dosage form relying solely on diffusion for delivery.

[0099] The dosage form also advantageously utilizes a solid drug formulation and does not need to house a liquid vehicle for the drug and the larger payload / capsule volume that would be required by the liquid vehicle. Providing the drug in solid form instead of liquid may advantageously facilitate higher drug loading and / or better stability during storage (especially for biologies or vaccines). This could potentially prevent the need for cold-chain storage of thedevice: a drug that needs to be stored in the cold chain while in a liquid solution could instead be packaged in the capsule in a solid state, where it could be stable outside the cold chain. In addition, making a capsule with a liquid inside is complicated and limits formulation options, since one needs to make sure that the liquid does not dissolve the capsule wall or get incorporated into the capsule wall and alter its properties.

[0100] In some embodiments, the dosage form for administration of a drug to a patient includes (i) a capsule comprising a capsule wall defining an interior space; (ii) drug particles disposed within a first portion of the interior space adjacent a pre-defined area of weakness in the capsule wall; and (iii) an excipient composition located within the interior space, wherein (a) the excipient composition is configured to react, or phase change, to produce a gas which pressurizes the interior space, and (b) the pre-defined area of weakness in the capsule wall is configured to rupture under the gas pressurization, forming a release aperture in the capsule wall through which the drug particles are ejected together with the gas. That is, the pre-defined area of weakness in the capsule wall is configured to rupture at a predetermined pressure by the gas pressurization. The excipient composition may be disposed within a second region of the interior space, separate from the first region and the drug particles, or alternatively, some or all of the excipient composition may be mixed with the drug particles. In a preferred embodiment, at least part of the capsule wall is configured to permit water to diffuse therethrough and contact the excipient composition, and the excipient composition is configured to react with the water to produce the gas. The capsule may be configured for oral administration to the patient. The patient may be a human or other animal.

[0101] The interior space of the dosage form is initially unpressurized, e.g., it may be substantially at atmospheric pressure. Then, as the gas is generated within the capsule in vivo, the interior space becomes pressurized and eventually reaches a critical pressure that causes the pre-defined area of weakness in the capsule wall to rupture, forming the release aperture through which the gas is expelled together with entrained drug particles. In a preferred embodiment, the dosage form is configured to eject the drug particles with a velocity sufficient to be effective to drive the drug particles across a mucosal barrier (e.g., the MC and / or the ECL) of an intestine within the gastrointestinal tract. This may be achieved by configuring the device to achieve a delivery pressure in the range between 30 - 170 kPa and a high ejection velocity', which may depend on a variety of tunable design parameters, including release aperture diameter; material selection, degree of its crosslinking, and thickness of the capsule wall; choice and amount of excipient composition (e.g.. choice of effervescent materials); and selection and thickness of capsule coating materials.

[0102] The predefined area of weakness (PAW) in the capsule wall may be formed of a material (or composite of materials) that is mechanically weaker than the material (or composite of materials) forming the parts of the capsule wall beyond the PAW. For example, the PAW may be a wall, which may consist of a gelatin material, having at least one few coating layers than the rest of the capsule, or the PAW may be a wall, which may consist of a gelatin material, having at least one coating layer that is a different material and / or is applied in a different way than the coating layer(s) of the rest of the capsule. In another example, the PAW may be a single, uncoated wall consisting of a gelatin material, while the remainder of the capsule wall is a composite of a gelatin material coated with one or more materials, such as a mechanically reinforcing layer of a lacquer and / or other water permeable material. In another example, the capsule wall may be cross-linked while the PAW is uncrosslinked. In another example, the PAW and remainder of the capsule are constructed of the same materials, but the wall thickness of the PAW is less than the wall thickness of the remainder of the capsule. In still another embodiment, the PAW is an area of a coating over / in a hole fabricated in the capsule wall. These foregoing examples may be used in combination to design a capsule capable of withstanding pressurization and directing the eventual rupture to occur only at the PAW.

[0103] In some embodiments, the capsule wall comprises a pair of rounded ends and an elongated cylindrical sidewall therebetween. In a preferred embodiment, the PAW and the release orifice are located in the elongated cylindrical sidewall. This orientation may facilitate a direction of drug particle ejection that is perpendicular to the mucosal barrier and adjacent the capsule and thereby enhancing penetration of the ejected particles across the mucosal barrier to reach intestinal tissues, by allowing more particles to penetrate and / or allowing the particles to penetrate more deeply.

[0104] The PAW and the release aperture may have any dimension and shape suitable to produce, in combination with the pressurization, the desired velocity for ejecting the drug particles. In some embodiments, the release aperture is circular in shape and has a diameter between 0. 1 mm and 10 mm. In a preferred embodiment, the PAW and release aperture has a diameter between 0.5 mm and 2 mm. In some embodiments, the dosage form is configured to pressurize the interior space to a pressure from 30 kPa to 300 kPa, preferably from 100 kPa to 170 kPa, before the rupture of the PAW. Higher pressures are also envisioned in some embodiments.

[0105] The drug particles may include any suitable drug and may be of any size suitable for entrainment in the gas and passage through the release aperture during ejection. Suitableparticle sizes may range from 10 nm to 10 mm. In some embodiments, the particles may range in size from 10 nm to 100 nm. In some other embodiments, the particles may range in size from 10 pm to 100 pm. Generally, the largest particles would be the same size or smaller than the release aperture, which might be up to 10 mm. It is envisioned that a single particle could be pressed up against the release aperture that pops out when the orifice opens. Such a particle could be larger than the release aperture and serve as the plug that blocks the aperture until a threshold pressure is achieved (e.g., like a champagne cork). Smaller sized particles maydissolve faster once ejected, which may be advantageous in some embodiments.

[0106] The drug may be a small molecule drug or a biologic. As used herein, the term “biologic” refers to therapeutic or prophylactic biological products including those isolated from a variety of natural sources - human, animal, or microorganism - or produced by biotechnology methods. The composition of the biologic may include genes, RNA, DNA, proteins, peptides, or nucleic acids or complex combinations of these substances, as well as cells and tissues. Non-limiting examples include insulin, blood products, vaccines, stem cells, immunotherapeutics, monoclonal antibodies, biological immunosupressants, biological disease-modifying antirheumatic drugs, enzymes, cytokines, hormones, and antibody-drug conjugates. The drug particles may include one or more pharmaceutically acceptable excipients and / or may include two or more different drugs.

[0107] In some preferred embodiments, the excipient composition within the capsule includes any suitable material(s) capable of reacting, or undergoing a phase change, to produce a sufficient quantity of gas to pressurize the interior space to reach the critical pressure needed to rupture the pre-defined area of weakness. In some embodiments, at least part of the capsule wall is configured to permit water to diffuse therethrough and contact the excipient composition to produce the gas. For example, the excipient composition may react with the water, or alternatively the water may enable two or more other reactants in the excipient composition to come into contact and react with each other, or the water may cause a change in pH which allows a reaction to occur. In a preferred embodiment, the excipient composition is configured to undergo a reaction with water to produce CO2 gas. Other materials and reactions could produce other biocompatible gases such as O2, N2, or H2. In one embodiment, the excipient composition includes or consists of an effervescent powder, including an acid component and a base component. The acid component may include citric acid, tartaric acid, fumaric acid, ascorbic acid, acetic acid, malic acid, lactic acid, phosphoric acid, or a combination thereof. The base component may include sodium bicarbonate, sodium phosphate, sodium carbonate, calcium carbonate, magnesium carbonate, potassiumbicarbonate, or combinations thereof. In a particular embodiment, the effervescent powder comprises citric acid and sodium bicarbonate. In some specific embodiments, the capsule, which may range in size from a size 3 to a 000 capsule, may contains from about 30 mg to about 200 mg of citric acid monohydrate and from about 44 mg to about 250 mg of sodium bicarbonate. The acid and the base components may be in particulate form and may be mixed together forming the excipient composition. The excipient composition may be compacted within the capsule or otherwise positioned to maximize contact of the excipient composition with the interior surface of the capsule wall. In various embodiments, the reaction or phase change may be initiated (i) by an influx of water (or other biological liquid) into the capsule which contacts the excipient material, (ii) by a change in pH of the aqueous liquid entering the capsule, and / or (iii) by a change in temperature and / or pressure within the interior space.

[0108] The dosage form may include one or more features to help control when gas generation occurs, specifically to mitigate premature reaction of the excipient composition and gas generation. In some embodiments, the excipient composition is in a dry powder form, which advantageously may remove free water molecules that might otherwise be present in the excipient materials, which could initiate the reaction before it is intended. The term “dry powder form” means substantially no free water; a dry powder form of excipient may include bound water, such as in citric acid monohydrate. In some embodiments, the excipient composition further includes a non-reactive material configured to slow or delay the reaction with the water. The non-reactive material may serve as a temporary physical barrier between reactive components of the excipient composition. The non-reactive material may be in the form of a water-soluble, or water-swellable coating on one of the reactive excipient materials. Examples of suitable non-reactive materials include polyethylene glycol (PEG), mannitol, microcrystalline cellulose, polyvinylpyrrolidone (PVP), and tartaric acid. In some embodiments, the non-reactive material has a melting temperature of 37 °C or greater, so that it melts when placed within the patient’s body, thereby no longer physically blocking contact between the reactive components of the excipient with w ater and each other. Examples of such non-reactive materials include Witepsol™ wax or other glycerol esters of saturated fatty acids known in the art. In some embodiments, the barrier structure may be a thin film placed between different excipient composition component layers. In some embodiments, the barrier is a thin cup-shaped film, where one excipient component is placed within the cup-shaped film and the other excipient is placed around and outside of the cup-shaped film.

[0109] In some preferred embodiments, the dosage form includes internal structures that facilitate (i) wetting of the excipient composition, (ii) retention of the excipient compositionwithin the capsule during ejection of the drug particles from the capsule, and / or (iii) complete ejection of the drug particles. In some embodiments, the interior space includes a funnel structure which tapers toward the PAW and is configured to direct the gas and drug particles through the release aperture in the capsule wall. The smaller end opening of the funnel structure may be aligned with the release aperture. In some embodiments, the interior space further includes a filter membrane disposed between the regions of the interior space separating the excipient composition from the drug particles, which permits the gas to flow from the second region to the first region and out through the release aperture with the drug particles. The filter may be a woven or non-woven polymeric fiber material, such as one made from biocompatible and / or biodegradable materials (e.g., nylon, PLGA, etc.). In some embodiments, the interior space further includes a wicking structure to convey water from an interior surface of the capsule wall to the excipient composition. The wicking material may be a porous material which maintains contact with the interior surface and the excipient composition regardless of the orientation of the capsule within a patient’s body. Examples of suitable wicking materials include natural and synthetic fibers, fabrics, and films, and biocompatible and water insoluble polymeric materials.

[0110] The capsule and capsule wall may be made of any suitable material(s). In particular embodiments, the capsule includes or consists of one or more bioerodible materials. As used herein, the term "bioerodible" means that the structure / material degrades in vivo by dissolution, enzymatic bond cleavage, hydrolysis, erosion, resorption, or a combination thereof. The capsule wall may include a cross-linked, biocompatible polymer. In some embodiments, the capsule wall includes a gelatin, a cellulose derivative (e.g., hydroxypropyl methylcellulose), or another cross-linkable and biocompatible material, such as those used to make conventional capsules in the pharmaceutical industry. The gelatin may be cross-linked to enhance its mechanical strength to withstand pressurization. For oral delivery, the capsule may be a size 000 capsule or smaller.[OHl] In some embodiments, the capsule is made of gelatin and then crosslinked using ultraviolet (UV) light throughout all of a portion of the capsule wall, except for the PAW in the capsule wall. Gelatin crosslinking may be effective to increase capsule wall stiffness and / or to prevent gelatin dissolution. Such hardened gelatin capsules may be particularly useful in the present dosage forms to resist thermal and enzymatic degradation, and / or to change the capsule solubility. The extent to which the capsule is crosslinked may be determinative of the amount of pressure buildup within the capsule before rupture of the PAW.

[0112] The capsule may consist of two or more parts that may be joined together after the contents are loaded within it. For example, there may be two capsule halves which can be secured together, partially overlapping one another in the middle region of the capsule. The parts may be sealed together by a biocompatible adhesive, tape, or solvent welding, as know n in the art. In some embodiments, the adhesive is curable with UV light and may be cured in less than one minute.

[0113] The capsule wall may include one or more coatings. In some embodiments, at least one of the one or more coatings covers the entire capsule except for the PAW.

[0114] The capsules may be coated in water-resistant polymer or lacquer. The gas generation builds up internal pressure within the capsule, which pushes against the capsule walls. Because the capsule body is relatively rigid and therefore as gas is generated the gas pushes against the rigid wall thus increasing pressure. In particular embodiments, the PAW eventually pushes outwards and finally bursts when a sufficient pressure is reached. That is, the pressure build-up causes a weakness made in the water-resistant polymer or lacquer coating (exposed gelatin delivery’ orifice) to burst, which pushes drug into the small intestine at increased velocities. In some embodiments, a polymethacrylate enteric coating is provided on top of the lacquer coating. Part of the lacquer coating can be exchanged for a polyurethane coating, and effervescent excipients can be pre-dried to allow for stabilization of the capsule for longer storage times. Enteric coatings, which are known in the art, can be added to the capsule to delay release based on pH of the gastric or intestinal fluid for selective release in the duodenum, small intestine, or colon.

[0115] The coating may be made from one or more biocompatible and / or biodegradable hydrophobic materials dissolved in an organic solvent. For example, the coating may be made from poly-(lactic-co-gly colic) acid (PLGA). poly-(lactic) acid (PLA), poly caprolactone (PCL), polystyrene, and / or polyvinylpyrrolidone (PVP). The organic solvent may be chosen to not dissolve the capsule body, or the other coatings already coated on the capsule body.

[0116] In some embodiments, at least one of the one or more coatings is an enteric coating, which can be used to help delay release until the dosage form passes to a certain region within the gastrointestinal tract. The enteric coating may function by serving as a temporary barrier to water entering the capsule to initiate the gas-generating reaction. The enteric coating may exclude or delay w ater entry’ in the relatively low pH environment of the stomach, and permit water entry w hen the dosage form is w ithin the relatively higher pH environment of the small and / or large intestinal tracts. For example, the coating may only be dissolvable when exposed to the stomach, duodenum, small intestine, or colon, having a pH range between 1.5 and 8. Forexample, the coating may be made from one or more polymers, including but not limited to methacrylic acid-ethyl acrylate copolymer (like Eudragit polymers), hydroxypropyl methyl cellulose phthalate (HPMCP), diethyl phthalate, cellulose acetate phthalate, and polyvinyl acetate phthalate. The polymer can be dissolved in organic solvent, chosen so application of the enteric coating does not dissolve the other polymer coatings already coated on the capsule body. In some embodiments, the enteric coating may be used to delay release of the drug formulation from the capsule. In other embodiments, the enteric coating may be effective to increase the pressure buildup within the capsule by extending the reaction time of the gas generating excipients, thereby increasing the strength of the burst release of the drug from the capsule.

[0117] In one embodiment, the coating is a water-absorbent polymer coating which permits water absorption while imparting structural reinforcement to the capsule wall. Such a coating may be applied to the entire capsule or to only is a portion of the capsule. In one case, increased water absorption into / through the capsule wall may be facilitated by the coating, particularly if positioned directly over the part of the capsule in which the excipient composition is located, which could be useful to increase the speed of an effervescent reaction of the excipient composition.

[0118] The dosage form may be configured to eject the drug particles within a gastrointestinal tract of the patient. In some embodiments, the dosage form is configured to eject the drug particles after a period between 1 minute and 6 hours, preferably from 10 minutes to 4 hours, following oral administration to the patient. A preferred target range is from 10 minutes to 2 hours. In some embodiments, the dosage form is configured to eject the drug particles at a predetermined position within the gastrointestinal tract following oral administration of the dosage form, wherein the predetermined position within the gastrointestinal tract may be the small intestine or colon of the patient. In preferred embodiments, the drug particles and gas are ejected from the capsule with sufficient pressure and velocity7to transport the drug particles across the mucosal membrane within the gastrointestinal tract. The optimal pressure within the capsule for high velocity drug delivery may be between about 30 kPa to about 300 kPa. more preferably between about 100 kPa to about 170 kPa. The dosage form may be configured to release the drug specifically within the stomach, small intestine, duodenum, ileum, jejunum, or colon.

[0119] FIGS. 1-3 depict one embodiment of a dosage form, which may be an oral dosage form. As shown in FIG. 1, the dosage form 100 includes a capsule 102 which has a top portion 104 and a body portion 106 that, when assembled, form the capsule 102. When assembled, thecapsule 102 has a unitary' capsule wall 108 having an elongated cylindrical wall 110 capped by a pair of rounded ends 112. A pre-defined area of weakness 114, which is configured to rupture under pressurization of a gas formed within the capsule 102. An adhesive may be used to seal the top portion 104 and the body portion 106 of the capsule 102. The top portion 104 and the body portion 106 of the capsule 102 may sealed together via application of a coating (not shown) to the exterior of the capsule 102.

[0120] The capsule 102 also includes a drug compartment 116. The drug compartment 116 includes a delivery orifice 118 through which the drug may be released from the capsule 102 into the body, upon rupture of the pre-defined area of weakness 114. The drug compartment 116 may be integrally formed with the body portion 106 of the capsule 102, or. as shown in FIGS. 2A-2C, the drug compartment 116 is formed as a separate component from the body’ portion 106 of the capsule 102. As shown in FIG. 2 A, the drug compartment 1 16 is sized to fit within the body portion 106 of the capsule. To assemble the capsule, as shown in FIGS. 2B, the drug compartment 116 is placed within the body portion 106 of the capsule 102, so that the delivery orifice 118 is aligned with the pre-defined area of weakness 114 of the capsule wall 110. After the drug compartment 116 has been placed within the body portion 106, the top portion 104 is fit onto the body portion 106 to complete assembly of the capsule 102, as shown in FIG. 2C. When the capsule 102 is assembled, the top portion 104, body portion 106, and drug compartment 1116 form a unified body.

[0121] Referring now to FIG. 3. the dosage form 100 is depicted in greater detail. In embodiments, the capsule 102 defines an interior space 120 within which the internal components of the capsule 102 are housed. Within the interior space 120, a first interior portion 122 may house the drug payload 126 and a second interior portion 128 may house the excipient formulation 130. The first interior portion 122 may include the drug compartment 1 16, which includes a funnel-shaped chamber 124 containing the drug pay load 126 therein. The funnel-shaped chamber 124 is in contact with the delivery orifice 118 in order to facilitate expulsion of the drug pay load 126 from the capsule.

[0122] As shown in greater detail in FIGS. 4A-4B, the drug compartment 116 includes a filter 132 to cover the wide opening 125 of the funnel 124. The filter 132 serves as a barrier between the drug payload 126 and the second interior portion 128 of the capsule 102. The filter 132 also may help prevent release of the excipient composition and any non-gaseous reaction products contained within the capsule 102 other than the drug payload 126.

[0123] The second interior portion 128 of the capsule houses a gas-generating excipient composition 130. The excipient composition 130, when contacted with aqueous liquid causesformation of gas which creates a pressure build-up within the capsule 102 to facilitate release of the drug pay load 126.

[0124] As shown in FIGS. 5A-5C, the second interior portion 128 of the capsule 102 includes a barrier to separate different excipients components of the excipient composition 130 for example to prevent premature reaction of those excipient components with one another. As shown in FIGS. 5A-5B, the barrier may be a divider 134 to separate a layer of a first excipient component I 30A from a layer of the second excipient component 130B. As shown in FIG. 5C, the barrier 134 may be in the form of a cup-shaped insert 136, where the first excipient 130 A is disposed around the cup-shaped insert 136 and the second excipient 130B sits within the cupshaped insert 136. Should more than two excipients components be included in the excipient formulation 130. additional barriers may be provided as needed.

[0125] As shown in FIGS. 6A-6D, the pre-defined area of weakness 114 may be formed through selective application of one or more coatings to the exterior of the capsule 102. In some embodiments, as shown in FIG. 6A, a coating 202 may be applied to the capsule wall 108 in all areas except the portion of the capsule wall 108 adjacent to the delivery orifice 118. In other embodiments, as shown in FIG. 6B, a preliminary coating 204 may be applied to the entire exterior of the capsule 102, and prior to application of the primary coating 202, which is applied in all areas except that adjacent to the delivery orifice 118. In further embodiments, as shown in FIG. 6C, the capsule wall 108 includes a cutout 109 through which the portion of the funnel 124 adjacent the delivery orifice 118 extends, such that the delivery orifice 118 is flush with the outside of the capsule wall 108. A coating 202 may then be applied to the entire exterior of the capsule 102, covering both the capsule wall 108 and the deliver}' orifice 118. Alternatively, as shown in FIG. 6D, a cutout 109 may be present in the capsule w all 108: however, the delivery orifice 118 remains within the interior space 120 of the capsule. A coating 202 may then be applied only to the space within the cutout 109 of the capsule w all 108.

[0126] FIG. 7 depicts a process of releasing drug particles from the dosage form, according to one embodiment. As shown in the illustrated sequence: (i) the capsule 102 contains a drug particle payload 126 and an excipient composition 130 is ingested and exposed to aqueous fluid within the patient: (ii) water diffuses through the wall of the capsule 102 and contacts the excipient composition 130 which then generates a gas, for example by undergoing an effervescent reaction to generate CO2 gas, w ithin the interior space of the capsule 102; (iii) the additional gas 131 generated by the effervescent reaction builds up and pressurizes the interior space 120 within the capsule 102; and (iv) upon reaching a critical pressure the pre-definedarea of weakness 114 ruptures forming release aperture 115, through which the gas 131 and drug particle payload 126 are ejected at high pressure and velocity. The generated gas will be mixed with pre-existing gas in the interior space and will not be in isolated bubbles as shown in these images.

[0127] A variety of methods for administering a drug to a patient are enabled with the disclosed dosage forms. In some embodiments, the method includes: administering, for example via oral delivery, a dosage form as described herein into a patient in need of treatment or prophylaxis; and then ejecting the drug particles from the capsule of the dosage form toward target tissues, e.g., of the gastrointestinal tract, of the patient upon generation of a pressure within the dosage form sufficient to rupture the pre-defined area of weakness in the capsule wall of the dosage form. The drug particles may be ejected following a predetermined period after the administering of the dosage form, or the drug particles may be ejected following the dosage form reaching a predetermined position within the gastrointestinal tract, e.g., a region having a particular pH. In these ways, drug deliver}' may be delayed to selectively target the small intestine, duodenum, or colon, for example.

[0128] In some embodiments, the dosage form is configured to be self-administered. For example, the dosage form may be an oral dosage form that a patient can swallow following a prescribed dosage regimen. In some embodiments, the dosage form may be configured for other mucosal routes of administration to other parts of the patient’s body.

[0129] The dosage form may be configured and used to eject the drug particles toward any mucosal surface within a patient, including the mouth, nose, eye, vagina, or rectum. For example, the dosage form may be configured for buccal, nasal, or ocular administration or as a rectal or vaginal suppository. The dosage form may be configured for insertion into other tissue sites for local, regional, or system administration of the drug particles.

[0130] As used in this specification and the appended claims, the singular forms '‘a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. The term “about,” as used herein, indicates the value of a given quantity can include quantities ranging within 10% of the stated value, or optionally, within 5% of the value, or in some embodiments, within 1% of the value.

[0131] While the disclosure has been described with reference to a number of exemplary embodiments, it would be understood by those skilled in the art that the disclosure is not limited to such disclosed embodiments. Rather, the disclosed embodiments can be modified to incorporate any number of variations, alterations, substitutions, or equivalent arrangements not described herein, but which are commensurate with the spirit and scope of the disclosure.

[0132] The invention can be further understood with reference to the following nonlimiting examples.Example 1. Ex Vivo Model of Pressurized Nanoparticle Delivery — Experimental Setup.Model Pressurization Device

[0133] A pressurization device with an adjustable shooting pressure was custom built from small brass pipe type fittings (McMaster-Carr, Douglasville, GA) using components described in Table 1. To assemble the nanoparticle shooter, the chamber valve was fastened to the left tee connection and the nozzle valve was fastened to the right tee connection of the pressure chamber with the flow directions for each valve going from left to right. Next, the pressure gauge was fastened to the bottom tee connection of the pressure chamber.Table 1. Ex vivo pressurized delivery device manufacturer part specifications.

[0134] With the main body intact, the hose plug connector was fastened to the back of the shooter (chamber valve) and then the hose plug was fastened to the back of that connector.This served as the connection point to an air compress (Product C2002. Porter Cable, Jackson. TN) to pressurize the pressure chamber. The front of the nozzle valve threat was tapped with apipe thread die (24NF 3 / 8) to fit custom nozzle caps (Milwaukee Sprayer, Menomonee Falls, WI).

[0135] Nozzle caps had an internal conical chamber for loading drug payloads and a nozzle orifice diameter of 500 pm. Volume of the device pressure chamber was approximately 1.3 ml to roughly match the internal volume of a size 000 oral capsule (1.37 ml). This allowed for shooting of nanoparticles with similar volumes of pressurized gas that would be expected in size 000 capsules.Ex Vivo Pressurized Delivery

[0136] Small intestinal tissue was collected from pigs after slaughter (Holifield Farms, Covington, GA). Sections (4-8 cm long) of small intestinal tissue (jejunum or ileum) free from luminal contents were excised from the gastrointestinal tract, flushed with ice-cold lactated Ringer’s solution (Henry Schein, Melville, NY), and placed in ice-cold lactated Ringer’s solution for up to 3h until use. For ex vivo preparation, fat and any leftover mesentery was removed, and a 1 cm length section of small intestinal tissue was cut open along the mesenteric line to expose mucosa for nanoparticle delivery.

[0137] Nozzle orifices were coated with a thin layer of lacquer formulation and left to dry for 30 min. The lacquer formulation was made fresh with 12.5% v / v lacquer (Rust-Olem, Concord, Canada), 87.5% v / v thinner solvent (Klean Strip, Memphis, TN). Approximately 0.5 mg of 20, 200, or 1000 nm nanoparticles were then loaded into the nozzle caps, which were fastened onto the nanoparticles shooter. Nanoparticles were selected for these studies to have particles that could fluoresce and be imaged and would be big enough to stay in place and not diffuse so that the deposition location could be determined. Pipe lubricant (RectorSeal, Tplus2, Houston, TX) was placed on the valve pipe threads immediately before nozzle fastening to ensure the nozzle cap chamber was airtight. The nanoparticle shooter was connected to the air compressor and the nozzle cap chamber was airtight. The nanoparticle shooter was connected to the air compressor and the nozzle valve was initially left closed to prevent premature delivery'. The nanoparticle shooter chamber was then pressurized to the desired pressure (100, 135, or 170 kPa). Once pressurized, the chamber valve was closed, and the nanoparticle shooter was disconnected from the air compressor hose. Pressure in the pressure chamber was checked with the pressure gauge attached to the nanoparticle shooter to ensure pressure was correct and there were no leaks.

[0138] For nanoparticle delivery, an opened (exposed mucosa) tissue sample was placed on a plastic stage with a 1 cm2square hole cut out in the middle. The tissue sample was laid on top of the hole (basolateral side touching the base, luminal mucosa exposed to the air) so thatwhen pressured delivery took place there would not be a hard backing behind the tissue during delivery, thereby better stimulating the in vivo environment. The nanoparticle shooter was attached to a clamp stand and lowered until the nozzle was approximately 1 mm above the mucosa. For deliver}', the valve leading to the nozzle was quickly opened and nanoparticles were thereby ejected from the nanoparticle shooter into the tissue mucosa. Nanoparticles of 20, 200, and 1000 nm diameter were delivered into the tissue samples at 100, 135, or 170 kPa. Nanoparticles were also delivered topically to the mucosa with no pressure (diffusion) using a spatula. Control tissue samples were also prepared containing no nanoparticles or nanoparticle shooter treatment.Tissue Histology

[0139] After nanoparticle delivery, tissue samples were folded back to their original cylindrical / physiological orientation and placed in a cryoblock filled with optimal cutting temperature (OCT) compound (FisherScientific, Pittsburgh, PA). The cryoblocks were then snap frozen by being lowered into isopentane (Sigma Aldrich) cooled by liquid nitrogen. After snap freezing, samples were stored at -80°C until sectioning.

[0140] Tissue cryoblocks were sectioned with a Lecia 3050 S Cryostat (Lecia Biosystems. Bufalo Grove, IL). The blocks were placed inside the cryostat 30 min prior to sectioning to allow for tissue blocks to equilibrate to cryostat temperature (-13°C to -20°C). For sectioning, slices of tissues were discarded until nanoparticles began to appear in the tissue, which identified the site of delivery. After that, a 10 pm thick section was placed on a microscope slide every 100 pm until no more particles were visible (approximately 30-50 sections were collected per tissue sample over a distance of 3-5 mm). Slides were stored in a -20°C or a - 80°C freezer until staining.

[0141] Fluorescent Histological Staining - Tissue sections were thawed at room temperature (20-25°C) for 8-15 min, then washed in phosphate-buffered saline (PBS) diluted from 10X PBS concentrate (OmniPur, Sigma Aldrich) by slowly dipping the sides in and out for 15-30 s in at least three separate washes until OCT compound was completely removed from the slide, as determined by visual inspection. Excess PBS was removed with a Kimwipe tissue (FisherScientific). and hydrophobic ink was drawn around each tissue section using a PAP pen (Abeam, Cambridge, United Kingdom). Next, tissue sections were incubated in wheatgerm agglutinin (WGA) labeled with Alexa Fluor 488 (ThermoFisher) diluted in PBS, at a concentration of 10 pg / ml, for 1 h in a closed, humidified chamber at room temperature.After incubation, sections were washed by dripping slides three times in PBS, switching out to fresh PBS each time. Finally, excess PBS was removed, and tissue sections were incubatedwith anti-fade medium with DAPI (Vector Laboratories, Burlingame. CA) for 5-15 min and cover-slipped. The coverslip edges were sealed with clear nail polish and slides were stored at - 20°C.

[0142] Fluorescent Confocal Imaging - Slides were thawed at room temperature for 5-15 min then cleaned with 70% ethanol before imaging. Imaging was done using a Zeiss LSM 700 fluorescence confocal microscope (Zeiss, Oberkochen, Germany) using lasers to image DAPI (excitation / emission. 350 nm / 470 nm), WGA (excitation / emission. 490 nm / 525 nm). and nanoparticles (excitation / emission 596 nm / 615 nm). A first set of images was taken using a lOx magnification objective, imaging only WGA and nanoparticles (i.e., using the green and red color channels, respectively). Tile scans of the entire delivery site were taken of each tissue section.

[0143] Select slides identified as having deep nanoparticle penetration into the mucus barrier from each tissue block were then imaged again using 20x or 40x objectives, imaging DAPI (blue channel) as well as WGA and the nanoparticles. The lOx images were used to macroscopically observe the delivery of nanoparticles and their location with respect to the mucus barrier and villi of the small intestine. The 20x and 40x images were used to observe nanoparticles near the epithelial cell layer (ECL) and intestinal crypts.Image Analysis

[0144] 2D Image Alignment - All lOx images from the same tissue sample were aligned using a custom programmed image alignment Java application that allow the user to load all the images from a tissue sample and align them. Once images were aligned, a MATLAB program (MathWorks, Portola Valley, CA) exported the cropped aligned images of every deliver^' area in each tissue section of a tissue sample. Two separate image files were exported: lOx images with WGA and nanoparticle color channels visible, and lOx images with only the nanoparticle color channel visible.

[0145] Nanoparticle Delivery Quantification - Villi structures were outlined and mapped (approximating the border of the ECL) in 1 Ox images for each tissue section within a particular tissue sample. A MATLAB program was then used to quantify the percentage of nanoparticles within various distances (0-30. 30-75. 75-150. >150 pm) from the ECL border of each tissue section. Once all tissue sections for a particular tissue sample were analyzed, percentages of total nanoparticles in the tissue sample within each distance range were quantified. The result was a representative estimation of the total percentage of nanoparticles in a tissue sample with various distance ranges from the ECL after different delivery conditions.

[0146] 3D Image Reconstruction - ImageJ software (National Institute of Health, Bethesda, MD) was used to generate a two-dimensional (2D) stack of aligned lOx images showing both the mucus barrier and nanoparticles. These 2D stacks could then be converted into a 3D reconstruction of the nanoparticles within the tissue using a three-dimensional (3D) tool in ImageJ. This allowed for visualization of the 3D delivery' site in the intestine. The 2D and 3D stacks were used to quantify delivery site dimensions after pressurized delivery’.

[0147] Delivery Site Quantification - Delivery distance was quantified using a measuring tool on ImageJ comparing all the images within the 2D stack to determine approximate maximum delivery' distance of nanoparticles (20, 200, 1000 nm) delivery at various pressures (0, 100, 135, and 170 kPa). The same measuring technique was used to measure the delivery site dimensions in the 3D image stacks for each tissue sample, calculating the approximate length, width, and height of the nanoparticle distribution generated after pressurized delivery7.Data Analysis

[0148] Mean and standard error of the mean were calculated using the replicates from pressurized delivery samples and non-pressurized delivery samples. Unpaired t-test was performed to compare pressurized delivery to non-pressurized delivery at the various nanoparticle distance ranges from the ECL (0-30, 30-75, 75-150, and >150 pm) using GraphPad Prism 8 (GraphPad Software, La Jolla, CA). A distance of 0-30 pm from the ECL border was considered representative of delivery near or within the firmly adherent layer of mucus. A value of p < 0.05 was considered statistically significant.Example 2. Ex Vivo Model of Pressurized Nanoparticle Delivery — Analysis and Results.

[0149] Oral capsules to deliver biologies through the GIT barriers by self-pressurization and convective force were designed with attributes that meet physiological, therapeutic, manufacturing, and patient constraints (Table 2) for significant clinical potential. In the context of these constraints, a capsule design was sought that (i) self-pressurizes in the GIT to achieve a target pressure, (ii) mechanically fails at a specified capsule location at a specified pressure, and (iii) efficiently ejects the capsule payload at high velocity7.Table 2: Summary of capsule operational parameters and design constraints.

[0150] The following demonstrates how pressure-driven flow of lyophilized model drug payloads, such as nanoparticles, can increase transport across the mucus barrier of the small intestine. Since neither nanoparticle size nor delivery pressure had a significant effect on nanoparticle delivery efficiency close to the ECL ex vivo, this suggests that a variety of particle sizes containing drugs of, in principle, any molecular weight, could be delivered using 100-170 kPa pressure. This also suggests that delivery was by particles carried in a gas jet, not by ballistic delivery of individual particles. Self-pressurized capsules, designed based on ex vivo results, achieved the design criteria in Table 2, as shown through the in vitro and in vivo results. Although UV crosslinking significantly increased gelatin resistance to thermal and enzymatic degradation, gelatin mass loss became more apparent at longer incubation times, implying that capsule burst should occur well within the time before the delivery orifice dissolves due to gelatin degradation and dissolution.

[0151] Although in vivo studies showed faster BGL decrease for capsules than for subcutaneous (SC) injection, under normal conditions (without surgical procedures) there would be a lag time before delivery of a drug payload from the capsule due to the time it would take for the capsule to pass from the stomach into the small intestine. The shift in T max of plasma insulin from 30 min (SC injection) to 45 min (capsule delivery) could be due to sampling blood from the jugular catheter which measures systemic insulin, but insulin delivered via the small intestine would first go to the liver before systemic circulation.

[0152] In vivo tissue damage was superficial and localized to the delivery' site (-0.25-1 mm2). Pressurized delivery’ of at least 100 kPa caused damage to epithelial cells by either triggering them to shed after impact, or the impact itself immediately created disruptions in the ECL by dislodging and potentially destroying cells. Damage was expected to rapidly repair without causing long-lasting adverse effects, as previous studies showed rapid epithelial restitution of segments of the duodenum over areas much larger than the area of damaged cells at the delivery site.Optimizing Capsule Pressure

[0153] The first objective was to identify a range of pressures suitable for convective delivery across the MB of ex vivo porcine small intestinal tissue. Polystyrene nanoparticles were as a model drug payload because they diffuse slowly through the MB without convective enhancement, and an ex vivo pressurization device was designed to achieve a wide range of pressures. An assembled ex vivo pressurization delivery device, as previously described, was used to deliver nanoparticles (NPs) at varying pressures into porcine intestinal tissue ex vivo. First, an opened section of pig small intestine (white arrow) is laid over a 1 cm2square hole on a stage holder and a preloaded pressurized delivery device is lowered towards the mucosa for delivery. To initiate delivery', the delivery' valve is opened. As shown in FIG. 8, the tissue sample (i) is opened (ii) and nanoparticles are delivered with pressure directly into the mucus barrier (MB). Delivery is shown between two circular folds (CF). At the delivery site, nanoparticles reach the villi (iii).

[0154] Testing pressures between 30-350 kPa, it was observed that at pressures below 100 kPa, most nanoparticles remained inside the nozzle cap. For pressures above 170 kPa, nanoparticles were often pushed away from the tissue mucosa, likely due to backflow of air from the tissue surface. For nanoparticles delivered between 100-170 kPa, efficient delivery through the nozzle orifice and minimal backflow of nanoparticles was observed, so pressures of 100, 135, and 170 kPa were further investigated.

[0155] After shooting 200 nm nanoparticles at 170 kPa into porcine small intestinal tissue ex vivo, nanoparticles were localized at the site of pressurized delivery and distributed across the MB, with some nanoparticles seen near villi. Closer examination shows that tissue sections near the center of the pressurized delivery' site have a high concentration of nanoparticles and deep penetration of nanoparticles across the MB. Tissue sections near the edges of the delivery site have fewer nanoparticles, which are mostly distributed in the outer, loose layer of mucus. Greater magnification shows that a portion of the nanoparticles completely breached the MB and reached the ECL. These images indicate a 400 pm-wide region with concentrated nanoparticles deep in the MB near the ECL.

[0156] To quantify nanoparticle distance from the ECL, image analysis was performed after ex vivo pressurized delivery. Low-magnification images identify sites of NP delivery shown with and without staining of the mucus barrier and tissue. Higher-magnification images (from the boxed regions) were used to quantify the percentage of NPs within various distances from the epithelial cell layer (ECL). MATLAB was used to draw contours at various distances from the ECL border, which is 30 pm from the ECL. Three representative cross-sectional images taken across the entire tissue sample showing the mucus barrier and tissue and NPs,and with the green color channel removed to show only NP distribution below. The images from the tissue sample, were then stacked using ImageJ, and spaced apart by their respective distance from each other (100 pm).

[0157] It was found that without pressure, most (51.6%) nanoparticles were >150 pm from the ECL and only 1.8% were within 30 pm of the ECL. By contrast, pressurized delivery left only 26.5% of nanoparticles >150 pm from the ECL and drove -20% of nanoparticles within 30 pm of the ECL (FIGS. 9E-9F). Delivery < 30 pm of the ECL should place most nanoparticles in the firmly adherent layer of the viscous mucus, which has a slow turnover rate of hours to days. Therefore, delivery' < 30 pm of the ECL should enable retention of the nanoparticles at the site of delivery', thereby enhancing their delivery across the ECL.

[0158] Nanoparticles (NPs) (20. 200, 1000 nm) were delivered ex vivo via pressure (100, 135, or 170 kPa) into intestinal mucosa and the percentage of nanoparticles within various distance ranges from the epithelial cell layer (ECL) was calculated using confocal imaging of frozen tissue sections. FIG. 9 A shows the percentage of nanoparticles within 30 pm from the ECL when delivered at 100, 135 or 170 kPa (data not significantly different, p>0.68). FIG. 10B, shows the of nanoparticles (20. 200, or 1000 nm) within 30 pm from the ECL when delivered at any pressure between 100-170 kPa (data not significant p>0.44 ). Thus, neither nanoparticle size nor delivery' pressure within this range had a significant effect on nanoparticle delivery efficiency to < 30 pm of the ECL. suggesting that a variety of drug payload types may be delivered with the flexibility of delivery pressure.

[0159] Macroscopic observations after pressurized delivery of nanoparticles ex vivo suggest that a crater (a few mm2) containing nanoparticles was formed within the MB of tissue samples. The pulse of gas emitted from the capsule likely pushed mucus out of its path, creating this crater in the MB which is referred to as the "delivery site". Delivery site dimensions and distribution of nanoparticles (20-100 nm) within it were calculated from 3D image construction showing nanoparticle distribution in the intestinal tissue after delivery. Based on image analysis, delivery site dimensions were independent of pressure or nanoparticle size, and were typically between 1000-2000 pm in length, 150-700 pm in width, and 250-600 pm in depth (MB penetration depth). The asymmetry between the delivery site dimensions was likely due to the circular folds, which ran longitudinally along the tissue segment length, and likely provided a rigid structure that prevented the flow of pressurized air in transverse directions (referred to as the width dimension above).

[0160] After diffusional delivery, nanoparticles were mostly on the MB surface without evidence of a crater (FIG. 9A). After pressurized delivery, 3D nanoparticle deliverydistributions were observed throughout the crater with high concentrations of nanoparticles deep in the MB near the ECL (FIGS. 9B-9D). Delivery at pressures of 100. 135, or 170 kPa had similar nanoparticle distributions, with high concentrations of nanoparticles within 30 pm from the ECL towards the center of the tissue delivery site. Diffusional delivery only had 1-4% of nanoparticles <30 pm of the ECL throughout the tissue. These observations suggest that a large portion of the nanoparticles located adjacent to the ECL were concentrated in a small region in the center of the delivery site (corresponding to the bottom of the crater), while most of the nanoparticles located further from the center of the crater were further from the ECL. Deep MB transport of pay loads was typically confined to a small area at the center of where delivery' took place, irrespective of nanoparticle size or pressure amount.Assessment of Ex Vivo Delivery

[0161] To better understand the mechanism of high-velocity delivery by self-pressurized oral capsules in vivo, fluorescently tagged insulin and 20 nm nanoparticles were delivered to rat intestine with the same device used for ex vivo studies at 100 kPa. The ex vivo pressurization device was used to ensure identical delivery pressure was administered each time. Fluorescence confocal images of rat small intestinal tissue in areas where no pressure, insulin or nanoparticles were delivered were captured. Images were collected as a tile scan of 10 pm thick sections and are representative of 12 different images taken from 3 different rats. No disruptions of the ECL w ere observed, and the lumen of the tissue was free of cellular debris. After high-velocity delivery of insulin and nanoparticles at 100 kPa, marked disruptions to the ECL were observed. Cellular debris due to epithelial damage was dispersed along the top of the villi throughout the delivery' site. Beyond the edges of the delivery site, the ECL membrane and nuclei of the individual villi were undisturbed and generally free from cellular debris. Notably, the insulin and nanoparticle distributions seen in the rat intestinal tissue in vivo were similar to those observed in pig intestinal tissue ex vivo.

[0162] Tissue Damage - Damage from high-velocity delivery was highly localized to an area -500 pm across, where insulin and nanoparticles w ere mostly concentrated and evidence of ECL damage was seen. These disruptions of the ECL support the hypothesis that insulin can be rapidly absorbed into the capillaries beneath the ECL. Insulin and nanoparticles w ere dispersed among a mixture of cell membrane debris and nuclei, and below the delivery^ site intact cells and villus structures appeared undamaged, just a few hundred microns from the site of dramatic ECL disruption. These images suggest that pressurized delivery' caused superficial damage to the ECL, localized to the villi (not the intestinal crypts), that can facilitate rapid access of insulin to the intestinal vasculature. Delivery at 170 kPa in vivo show ed similar ECLdisruptions and insulin delivery' to 100 kPa delivery (FIGS. 11 A-l 1C), which suggests that delivery at 100-170 kPa is suitable to cause disruptions of the ECL to facilitate drug delivery. Intestinal tissue after passive delivery (for 30-60 min) showed insulin and nanoparticles localized above the villi away from the ECL, likely in the MB, and did not show any tissue damage or cellular debris, similar to untreated tissue (FIG. 13 A). Damage seen after pressurized delivery was therefore due to the high velocity delivery and not the insulin, nanoparticles or procedural artifacts.

[0163] H&E Staining - H&E staining shows dramatic damage to the ECL after pressurized delivery, which was highly localized to a single, microscopic area within the entire tissue sample, while the rest of the tissue exhibited well-preserved villi structures throughout (FIGS. 12A-12C). Magnified images at the delivery site showed clear disruptions of the ECL with cellular debris dispersed throughout the delivery site (FIG. 12B-12C). Beyond the edges of the delivery sites, the villi and ECL appeared unharmed. Images of successive tissue sections showed similar disruptions to the ECL, cellular debris dispersed throughout the delivery site, and intact epithelial layers with well-preserved villi beyond the edges of the delivery site (FIGS. 13A-13F). These images further support the observation that ECL damage is localized to a small surface area of mucosa measuring less than ~1 mm2.

[0164] Companion H&E images of intestinal tissue exposed to passive delivery' of insulin and nanoparticles showed no evidence of damage to the ECL throughout the tissue section (FIGS. 12D-12F). Images of successive tissue showed no signs of damage to the ECL or cellular debris (FIGS. 13G-13L). Taken together, these H&E and fluorescence confocal images suggest that damage to the ECL at the pressure delivery' site was highly localized and was a direct result of the pressurized delivery'.Example 3. Development of Pressurized Capsules for Nanoparticle Delivery

[0165] Informed by pressurized delivery properties needed to drive drug payloads deep into the MB, oral capsules were designed to achieve the target pressurized delivery properties based on a conventional oral gelatin capsule modified for self-pressurization in the GIT. The capsule was designed with four main components: (i) a gelatin capsule with a coating that provides mechanical strength to prevent mechanical failure during pressurization, (ii) a hole in the coating (delivery orifice) to provide a site of mechanical weakness through which the capsule pay load can be ejected at a specified failure pressure, (iii) a drug compartment that contains the drug in the capsule and facilitates its efficient release from the capsule upon opening of the delivery' orifice, and (iv) excipients within the capsule that generate CO2 gas to pressurize the capsule due to contact with water in the GIT.Self-Pressurized Oral Capsule Design and Fabrication

[0166] Enabling the gelatin capsules to self-pressurize and eject drug particles involved three main components: (i) a coating with a deliver}' orifice (orifice from which the drug was propelled), (ii) a drug compartment to hold the drug, and (iii) excipients to generate pressure upon contact with water.

[0167] Oral Gelatin Capsules - Size 000 and 0E pharmaceutical-grade bovine gelatin capsules (Capsuline. Dania Beach. FL) were used with internal volumes of 1.37 ml and 0.78 ml, closed lengths of 26. 1 mm and 23.5 mm, and diameters of 9.91 mm and 7.65 mm, respectively, according to manufacturer's specifications. Their caps were 12.95 mm and 11.66 mm long, and their bodies were 22.2 mm and 11.68 mm in length for the 000 and 0E capsules, respectively. Shell thickness was measured as 0. 11 ± 0. 1 mm for both capsules by light microscopy (Olympus SZX16, Olympus Lifescience, Parkway Center Valley, PA).

[0168] Gelatin Crosslinking - Gelatin capsules were separated into their caps and bodies, placed on an aluminum foil-lined stage attached to a shaker and exposed to ultraviolet (UV) light (Model RRD 12-4S, Atlantic Ultraviolet, Hauppauge, NY). The UV crosslinker contained four bulbs (233 mm length, 12.4 W total output) emitting light with 253.7 nm wavelength. Capsules were crosslinked for 0, 10, 25, or 50 h, denoted as NC (no crosslinking) UV10, UV25, or UV50, respectively. The shaker was set at 900 rpm to move capsules during irradiation to facilitate spatially uniform crosslinking of the gelatin capsules. After UV irradiation, capsules were stored in a sealed container at room temperature and humidity (30- 60% rh).

[0169] Capsule Coating - Non-crosslinked and cross-linked capsule caps and bodies were dip coated with a think lacquer-based solution and left to dry at room temperatures and humidity for at least 2 h.

[0170] Delivery Orifice - Double-sided adhesive tape with a paper backing (3M, Northridge, CA) was attached on one side to an aluminum foil sheet and cut into 2 cm squares. A single hole was cut out of the center of the resulting foil mask (through the foil, adhesive and paper backing) using a 0.5 mm (WellTech, Taichung, Taiwan), 1 mm (WellTech), or 2 mm (IntegraLife, Princeton, NJ) diameter biopsy punch. The paper backing of the foil mask was then removed, and the exposed adhesive side was applied to a coated capsule body, positioning the biopsy hole 5-8 mm from the bottom edge of the capsule. To provide mechanical support, a metal rod of similar diameter was inserted in the capsule body throughout this process. The foil mask was secured onto the capsule body by pressing the area around the hole down with a small metal spatula to ensure firm adhesion.

[0171] Next, lacquer thinner solvent (Klean Strip) was applied to the portion of the gelatin capsule body exposed where the 0.5 mm, 1 mm, or 2 mm hole was made with a cotton tip applicator dipped in the lacquer thinner. The cotton tip was rubbed over the hole to remove the lacquer coating 10-14 times (for 0.5 mm hole) or 5-7 times (for 1 mm and 2 mm holes). This cleaning process was then repeated. The foil mask was then wiped with a Kimwipe tissue to remove residual solvent and left to dry for at least 2 min, and then carefully peeled off. This process produced a fully coated capsule body with a 0.5 mm, 1 mm, or 2 mm diameter hole (i.e., delivery orifice) in the coating, about 5-8 mm from the bottom edge. This delivery orifice was far enough toward the bottom of the capsule body that when the capsule cap was secured to the capsule body it did not cover the delivery orifice.

[0172] Drug Compartment - The drug compartment was designed using SolidWorks software (Dassault Systems, Velizy, France). The drug compartment was a semi-cylinder (radius 4.55 mm, length 10 mm) with a flat surface (width 9.91 mm, length 10 mm) containing a 0.5 mm, 1 mm, or 2 mm diameter hole (delivery orifice) through the center of the flat surface all the way through the semi-cylinder. A chamber cut around the delivery orifice hole 45 degrees, 2.5 mm in length) on the flat surface was included to create a cone chamber in the drug compartment that provided space in which to load the drug. Prototypes of the drug compartment were 3D printed (Object24, Stratasys, Eden Prairie, MN) from Verowhite Plus plastic material. Nylon net filters, 20 pm pore size (Sigma Aldrich) were secured to the bottom of the drug compartment on the flat surface of the cylinder with UV curable acrylic adhesive (RapidFix, Carlsbad, CA).

[0173] Biodegradable prototype drug compartments were made using a mixture of 50% w / w silicified microcrystalline cellulose (JRS Pharma, Rosenberg, Germany) and 50% w / w poly (ethylene oxide) (POLYOX WSR NlOChemPoint, Bellevue. WA) that was poured into a 1 cm inner-diameter aluminum tube and compacted with an aluminum rod slightly less than 1 cm in the outer diameter using a manual hydraulic press (Devin Manufacturing, Arcade, NY) at approximately 7 MPa. The conical chambers for holding the drug w ere then created in the compacted power cylinders using a Dremel tool kit (Dremel, Racine, WI).

[0174] Excipients - A mixture of 228 mg sodium bicarbonate (NaHCCh. Sigma Aldrich) and 191 mg citric acid monohydrate (CA, Sigma Aldrich) was packed tightly inside the bottom of the capsule body with a steel rod (diameter 9 mm). These excipients w ere used to generate pressure in the capsule by chemical reaction with water to generate CO2 gas:C6H807■ H20(aq) + 3NaHCO2s) -> 4H2O(Z) + 3CO2g) + / VaC6H507(aq)

[0175] Capsule Assembly - To assemble a complete capsule, NaHCCh and CA were packed into the capsules. A drug compartment was then filled with the desired amount of model drug (through the delivery orifice) and then placed inside the capsule body. The delivery orifice of the drug compartment inside the capsule was aligned with the delivery orifice in the coating on the capsule, and then secured in place with UV-curable acrylic adhesive. Finally, a coated capsule cap was secured onto the capsule body and sealed with UV-curable acrylic adhesive on the inside wall of the capsule cap to make an air-tight seal.

[0176] Model Predictions - Additional modeling of the capsules, and optimization of the delivery pressure and velocity is described in greater detail in “High Velocity Delivery of Biologies from Self-Pressurized Oral Capsules to the Gastrointestinal Tract” by Joshua Palacios (https: / / hdl.handle.net / 1853 / 71943). FIGS. 14A-14D summarize the model predictions for crosslinked gelatin elastic modulus and capsule performance.Self-Pressurized Oral Capsule Performance

[0177] The first goal was to design a capsule that that was mechanically stable during the pressurization process and only fails at a specific location. A five-step process was developed to fabricate a mechanically stable capsule with a pre-engineered failure point (delivery orifice). First, conventional gelatin capsules were crosslinked (UV irradiation, 254 nm) which increases mechanical strength and thus prevents thermal and enzy matic degradation, and dissolution in the GIT. Crosslinked capsules were then dip-coated with lacquer to strengthen the capsule to prevent mechanical failure during pressurization. After solvent was selectively applied to the coated capsules, the result was an uncoated gelatin delivery orifice on the capsule body surrounded by a lacquer coating on the rest of the capsule surface.

[0178] The second goal was to store and position drug payloads for efficient release from the capsule upon failure of the delivery orifice. Drug compartments were designed that (i) separate the drug from excipients in the capsule with a conical funnel that holds the drug, (ii) allow- the passage of CO2 gas into the drug compartment but prevent the leaking of drug into the capsule, enabled by a filter membrane covering the funnel, and (iii) facilitate rapid release of drug from the capsule upon delivery’ orifice failure by aligning the narrow end of the funnel with the delivery orifice. Prototypes were 3D printed with non-biodegradable polymer resin or made from compacted silicified microcrystalline cellulose and poly(ethylene oxide), which are biocompatible biodegradable excipients used in oral tablet formulations.

[0179] The final goal was to initiate the delivery' process by generating pressure within the capsule in a safe and biocompatible manner. Gas -generating excipients, sodium bicarbonate (NaHCCh) and citric acid (CA), were chosen because they are safe to ingest and are commonlyused in oral tablet formulations. Only when the capsule is in gastrointestinal fluid, water should begin to flow into the capsule coating and gelatin shell by osmosis. Excipients in contact with the gelatin wall will then react, producing CO2 gas, thereby pressurizing the capsule.

[0180] The effect of UV-crosslinking time on gelatin water absorption, thermal stability, and enzymatic stability was further characterized. Water absorption of uncoated and coated capsule bodies were incubated in room temperature and 37 °C water, respectively. Increased UV crosslinking significantly reduced water absorption of gelatin at room temperature compared to non-crosslinked gelatin (FIG. 15 A), consistent with prior studies. As expected, lacquer coating of capsules dramatically suppressed water absorption of gelatin (FIG. 15B). Crosslinking also significantly improved gelatin resistance to both thermal (FIG. 15C) and enzymatically driven dissolution in SIF (FIG. 15D).

[0181] The delivery pressure of capsules was also determined as a function of gelatin crosslinking time and delivery orifice diameter. Capsule delivery pressure significantly increased with increased crosslinking time (FIG. 15E) since crosslinking gelatin allowed for less water absorption and dissolution. Delivery pressure also significantly increased with a smaller delivery orifice diameter because a smaller orifice requires a larger pressure to produce the same orifice deflection that will cause failure, as expected from prior studies. By varying crosslinking time and delivery' orifice diameter, delivery' pressures were modulated between -30-170 kPa, enabling fine control of delivery pressure. In addition to 000 capsules, 0E capsules were also tested and showed similar delivery pressure trends (FIG. 15F). No significant difference in delivery’ pressure between the 000 and 0E capsules with the same crosslinking time and delivery' orifice was observed, consistent with the expectation that size and mechanical strength of the delivery orifice governs delivery' pressure. It was also observed that time to capsule delivery increased with delivery’ pressure, because more time was required to build up higher pressures within the capsules. Delivery pressures and time measured in water at 37 °C showed similar trends as seen in SIF (FIGS. 16A-16D).

[0182] Control studies of 000 capsules, UV crosslinked for different times, were also performed in water at 37 °C for 10 minutes to demonstrate the effects of various capsule configurations on maximum internal capsule pressures and deliveries (FIG. 16E). Lacquer coated capsules with no sodium bicarbonate (SB) or citric acid (CA) demonstrated no increase in internal capsule pressure from baseline. Similarly, lacquer coated capsules containing SB and no CA or containing CA and no SB demonstrated no increase in internal capsule pressure from baseline. This indicates the need for an excipient combination or configuration that is designed to react and produce a gas which pressurizes the interior space of the capsule.Uncoated capsules containing both SB and CA showed an increase of pressure between 52-57 kPa, achieving significantly lower pressures for UV crosslinked capsules when compared to FIG 16A. Visual observation revealed that uncoated gelatin capsule shells expanded irregularly until they eventually ruptured in random locations other than the delivery orifice (D.O.). This indicates that the capsule coating is able to prevent premature capsule failure and increase the capsule internal pressure while ensuring pressure delivery solely at the intended D.O., the predefined area of weakness in the capsule. Finally, capsules containing SB. CA, and a lacquer coating had their delivery orifices covered with superglue. These capsules reached the maximum measurable pressure of 300 kPa and did not rupture including at the D.O. which was super glued over. This indicates that a functional delivery orifice is needed to act as a predefined area of weakness to ensure pressure delivery occurs as intended in a predetermined location on the capsule.

[0183] Delivery velocity of payloads ejected upon capsule burst was determined using high-speed video recording, which shows a single burst of material from the delivery orifice that lasted ~ 70 ms, after which the plume released from the capsules continued to travel a few more millimeters over another 200 ms. The distance traveled by the released plume increased with decreasing orifice diameter (z.e., corresponding to higher delivery pressure), and more drastically with degree of crosslinking, since payloads from the UV50 capsules traveled ~2-4 times further than from non-crosslinked capsules. Delivery velocity similarly increased with decreasing orifice diameter and with increased crosslinking (FIGS. 17A-17B). Maximum velocity also significantly decreased with increasing delivery orifice diameter for the UV50 capsules, but not the NC capsules. Control studies were also conducted to better understand the mechanism of payload delivery from self-pressurized capsules (FIG. 17C).Example 4. In Vivo Delivery of Insulin via Self-Pressurized Oral Capsule

[0184] Guided by the self-pressurized capsule characterization in vitro, a surgical procedure was to place the engineered capsules in vivo in rat intestine loaded with human recombinant insulin. Rats were placed under anesthesia and a catheter was inserted in the jugular vein for continuous blood sampling. A surgical incision was made along the abdominal midsection of the rat and held open with hemostats while an intestinal loop, free of luminal contents, was located. An incision was made along the antimesenteric border of the intestinal loop with a micro-cauterizer. The incision of the intestinal loop was opened, and insulin was delivered topically onto exposed mucosa (passive delivery) or by high-velocity' delivery from a self-pressurized oral capsule by placing the pressurized capsule onto the surface of the exposedmucosa. 20 nm nanoparticles were then delivered at 100 kPa directly into the exposed mucosa of the small intestine.

[0185] The average delivery pressure of the capsules was 1 13 kPa, and no obvious damage to the mucosa was visually observed immediately after deliver}'. Deliver}' of insulin via capsules led to a rapid and sustained decrease in blood glucose level (BGL) until the end of the experiment almost 6 h after insulin delivery (FIG. 18 A). Insulin delivery by subcutaneous (SC) injection led to similar BGL reductions, but with slower kinetics. Insulin deliver}’ in the intestine by passive delivery, as well as the negative control procedure in which no insulin was used, had little effect on BGL. Delivery of insulin from capsules resulted in a rapid decrease in BGL from baseline measured 30 min after delivery, which was significantly lower than BGL after passive deliver}’ or no delivery (FIG. 18B).

[0186] The rapid decrease in BGL from capsules, compared to passive deliver}', is consistent not only with rapid convective transport across the MB, but also suggests a breach in the epithelial barrier was made due to the high-velocity deliver}' of insulin. Even with the expected increased transport of insulin across the MB, studies have shown that the transport rate of insulin across an intact ECL is slow. Because blood flow from the small intestine goes directly to the liver, rapid insulin delivery into the capillaries of the small intestine should trigger a rapid absorption of blood glucose by the liver, as was seen in FIGS. 18A-18B. Delivery of insulin via the capsules also led to an increase in plasma insulin concentration much greater than after passive insulin delivery, and similar to SC injection (FIG. 18C). The total insulin delivered (area under curve) for capsules was not significantly different from SC injections but was significantly higher than passive deliver ' (FIG. 18D).

[0187] At early time points, insulin delivery from self-pressurized capsule caused greater drops in BGL but had similar plasma insulin concentrations compared to SC injection (FIGS. 18A, 18C). This apparent discrepancy may be explained by clearance of insulin by the liver. Unlike SC injection, which delivers insulin directly into systemic circulation, insulin delivered via the intestinal vasculature goes directly to the liver. Thus, before insulin delivered by capsule in the intestine reaches systemic circulation (where insulin plasma concentration was measured) insulin was rapidly removed by the liver, reducing plasma insulin level and increased the drop in BGL.Surgical Procedure

[0188] Rats were fasted overnight with access to water before the non-survival surgical procedures. Rats were put under anesthesia (5% isoflurane) in a chamber and then transferred to a nose cone (2.5% isoflurane) with their back on a heating pad and abdominal side facingup. A jugular catheter connected to a blunt-tipped needle was inserted for continuous blood sampling, and then isoflurane was turned down to 1.5%. Baseline blood samples were taken at 30 and 60 min (referred to as BL75 and BL45, respectively) after that point. The blood samples were used immediately to measure blood glucose using a handheld glucometer (Contour Next One, Contour, Parsippany, NJ) and the rest of the blood was placed in lithium heparin blood tubes (BD, Franklin Lakes, NJ) and centrifuged to collect plasma. Hair from the abdomen was shaved and at 75 min (after isoflurane was decreased to 1.5%), isoflurane was increased to 2.5% and surgery was started. Toe pinch was done before abdominal surgery to check for pain before abdominal incision.

[0189] To perform abdominal surgery (total time 15 min), an incision was made down the midline of the abdomen and kept open with hemostats. A small intestinal loop, free of visible luminal contents, was located and placed on a small surgical pad. A micro-cauterizer was used to make an incision on the antimesenteric side of the small intestine between 1 - 2 cm in length. This incision was then opened with fine-tip forceps to expose the mucosa. Delivery of insulin was made to the exposed mucosa, and the incision was then closed using surgical glue (Henry Schein). The intestinal loop was then placed back inside the abdominal cavity and the abdominal cavity incision was closed with surgical glue. Isoflurane was decreased and maintained at 1.5% throughout the remainder of the study.Delivery Groups

[0190] Rats (n = 4 - 5 per group) were randomly assigned to four different treatment groups: no treatment (NT), subcutaneous injection (SC), passive delivery (P), and selfpressurized oral capsules (Cap). For the NT group, the surgical procedure was carried out without any delivery of insulin. For the SC group, the same surgical procedure was followed (without delivery of insulin into intestinal loop) and then a subcutaneous insulin injection was given into the back of the rat (0.5 IU insulin diluted in sterile saline). For the passive delivery group, lyophilized insulin (8.5 IU) was topically delivered to the mucosa of an intestinal loop using a spatula.

[0191] For the Cap group, size 000 capsules (0.5 mm delivery’ orifice diameter, UV10 crosslinked, lacquer-coated) were assembled as described above with ~8.5 IU of lyophilized insulin loaded into the drug compartment. A wireless pressure sensor was inserted into the capsule to record pressure inside the capsule. Capsules were pressurized in water at 37 °C before the start of the surgical procedure. Once capsules were close to reaching a critical pressure (100 kPa), the capsules were removed from the water and placed on the surface of the exposed mucosa of the intestinal loop with the delivery orifice facing the mucosa. To continuethe capsule pressurization process, warm water was pipetted onto the capsule surface opposite the mucosa. This process was used because size 000 capsules are too big to fit in the lumen of the rat intestine, so it was necessary to use water rather than the endogenous fluid in the rat intestine to generate pressure in the capsule.Blood Collection

[0192] Blood samples were taken through a 1 ml slip tip syringe (VWR, Radnor. PA) connected to the jugular catheter needle tip and then transferred into lithium heparin blood collection tubes (BD) and spun down by centrifugation. The catheter was flushed with fresh saline (Henry Schein) after every blood collection, and a new slip tip syringe was used for every blood sample. After centrifugation, blood plasma was collected and transferred into a cryotube and stored on dry ice. After all samples were collected, they were stored at -80 °C until analysis. Blood collection time points were as follows: baseline samples BL75, BL45 (75 min and 45 min before insulin delivery); BL 15 min (when the surgical procedure started, and 15 min before insulin delivery), 0 min (surgical procedure finished and insulin delivered); and then at 15, 30, 45, 60, 75, 105, 135, 165, 225, 285, and 345 min after insulin delivery.Animal Euthanasia

[0193] After the final time point was collected, rats were euthanized in a CO2 chamber. Then, the abdominal cavity was opened, and the small intestine was removed. The delivery site was located and distance from the stomach was measured. The tissue delivery site was examined to look for signs of adverse reaction, necrosis, or anything else notable upon visual inspection. Tissue was then collected for subsequent histology.Blood Glucose Measurement

[0194] Blood glucose was measured with a Contour Next One blood glucose monitoring system with approximately 1- 5 pL of blood placed onto a test strip. Glucose levels were stored on the Contour Next One phone app as well as recorded on procedural sheets. Baseline blood glucose levels were calculated by averaging the blood glucose levels of the three baseline blood samples before delivery (BL75, BL45, and BL15). Measured glucose levels were normalized relative to the baseline blood glucose level, and then percent blood glucose change was calculated relative to the normalized baseline blood glucose level of 1. Mean and standard error of the mean for percent blood glucose change were calculated using the replicates (n = 4- 5) for each treatment group (ND, SC, D, and Cap).Plasma Insulin Study

[0195] Plasma samples (time points 0. 30. 45. 60. 75, 115, 165. and 345 min) from 4-5 rats per group were sent to the Animal Health and Diagnostic Center (Cornell University, Ithaca,NY) for analysis. Insulin concentration was measured by radioimmunoassay for human recombinant insulin with 0.1% cross-reactivity with rat insulin. Mean and standard error of the mean for insulin plasma concentration were calculated using the replicates (n = 4-5) for each treatment group (ND, SC, D, and Cap). Area under the curve (AUC) was calculated for each rat within each treatment group using Graph Pad Prism 8 and then mean AUC and standard error of the mean were calculated for each treatment group.Tissue Histology

[0196] Delivery site tissue was excised from the intestine and rinsed with ice-cold lactated Ringer's solution (Henry Schein), and Swiss rolled. The Swiss roll technique involves opening a tissue sample along the anti-mesenteric border and rolling it up longitudinally with the mucosa outwards using forceps. Swiss-rolled tissue samples were then placed into OCT compound and snap-frozen as described for the ex vivo tissue histology. Tissue was stored at - 80 °C until sectioning. Sections measuring 10 pm thick were prepared with a cryostat, placed onto glass microscope slides, and stored at -20 °C. For staining, tissue sections were thawed at room temperature for 5-15 min, and then fixed with fresh Carney's solution at 4 °C for 15 min. Sections were then dned at room temperature for 10-15 min, stained with hematoxylin and eosin (H&E) staining kit (Abeam) following manufacturer protocols, and finally cover-slipped with Cytoseal 60 resin (FisherScientific).H&E Imaging

[0197] Sections were imaged using an AxioObserver Z1 fluorescent microscope (Zeiss) with tile scans encompassing the entire tissue sections.Example 5. Optimization of Capsule DesignFilter Membrane

[0198] The filter membrane adhered to the back of the funnel of the drug compartment was modified to allow for better translation to in vivo studies. The filter membrane was made smaller and glued deeper into the funnel of the drug compartment to allow the drug / payload to be closer to the inside of the delivery orifice. This could allow for better delivery efficiency in terms of the amount of drug that leaves the capsule upon capsule burst versus the amount of drug left behind inside the capsule.

[0199] The capsule was placed in the water with the delivery orifice pointed upwards to represent a possible orientation of the capsule in the small intestine. Previously, in vitro tests were conducted with the delivery orifice facing dow wards to help the payload stay as close to the inside of the delivery orifice as possible. With the new' filter membrane modification, thecapsule can be oriented in different positions and still have the drug held close enough to the inside of the delivery orifice for release from the capsule.Separation of Excipients

[0200] Another modification for eventual in vivo translation is adding a piece of paper on top of the compacted efferv escent excipients. The paper can be secured to the inside of the capsule by UV -curable glue. The paper can keep the excipients from losing contact with the inside of the capsule wall. If the excipients lose contact with the capsule wall, the excipients might not absorb enough water for effervescent reaction. The capsule is expected to change orientation as it transits through the gastrointestinal tract.Alternative Capsule Designs

[0201] Other methods besides the improvement (pre-drying excipients and adding Tecoflex coating and preparing in low-humidity chamber) were also tested to stabilize the capsules but were not tested as extensively as the improvement described above. The following methods were tested with capsules with the original lacquer coating only.

[0202] Separating the citric acid and sodium bicarbonate in different compartments of the capsule were tested by making thin films of inert materials to separate sodium bicarbonate from citric acid inside the capsule. The inert materials chosen were either water-soluble, or only melt above physiological temperature. Witepsol S55 wax (hard fat made from glycerol esters of saturated fatty acids commonly used in suppositories) is shown as an example of a film. The Witepsol film could act as a barrier between sodium bicarbonate and citric acid during storage, and only when placed in vitro or in vivo at physiological temperature (>35 °C), the film will melt to let the excipients come in contact and react. Or if using water-soluble materials, when the capsule is placed in liquid, the water-soluble materials could dissolve and let the excipients come in contact. However, the capsule did not absorb enough water to let a thin water-soluble film dissolve inside. A capsule-in-capsule design was tested by using a smaller 0E size gelatin capsule (without coatings or crosslinking) to contain the citric acid. However, the capsule did not absorb enough water to allow the 0E capsule inside to dissolve for the citric acid to come in contact with the sodium bicarbonate. Witepsol S55 was also tested for putting a thin coating around the mixed excipients so that when placed at temperature >35 °C, the Witepsol could melt and let the excipients touch. However, this reaction was too slow when tested in vitro. When only citric acid granules were coated in a Witepsol S55 matrix and then mixed with uncoated sodium bicarbonate, the capsule achieved a more significant pressure increase (FIG. 19).

[0203] Sodium bicarbonate was also tested with Witepsol coating and then blended with uncoated citric acid monohydrate. The capsules were stored for 3 days at room temperature or 4°C but capsules burst at a lower pressure than expected (FIG. 20) due to the slow reaction rate.

[0204] Different shaped Witepsol barriers between sodium bicarbonate and citric acid were also fabricated and tested, but did not have significant pressure increase when tested in vitro in SIF in fresh capsules. Testing demonstrated that while the barrier did melt, the sodium bicarbonate and citric acid did not have good contact with each other for reaction.

[0205] Other acids (that are less hygroscopic), such as fumaric acid or ascorbic acid, were also tested instead of citric acid monohydrate, but reaction rate was very slow in lacquer- coated capsules. Fumaric or ascorbic acid could be tested to replace the pre-dried citric acid monohydrate in the Tecoflex-coated capsule too.

[0206] Another method tested to stabilize capsules was coating citric acid and sodium bicarbonate in non-reactive excipients that would protect them from water absorption during storage, but could dissolve in vitro in aqueous solution. Citric acid monohydrate was coated in in polyethylene glycol (PEG1000) and granulated with microcrystalline cellulose and passed through a sieve. Sodium bicarbonate was blended with mannitol. These stabilized excipients were blended with untreated excipients at different ratios and resulted in different reaction rates in vitro.

[0207] This method of coating citric acid in PEG1000 and microcrystalline cellulose was also tested with varying ratios of the PEG1000, microcrystalline cellulose, and mixing ratios of the coated citric acid to uncoated citric acid. Various formulations were mixed with sodium bicarbonate and tested in vitro in SGF.

[0208] Another method tested was effervescent granulation, which works to partially pre-react the excipient mixture before fabricating and storing into the oral dosage form. This could help prevent pre-reaction during storage. Dry granulation was tested by mixing citric acid monohydrate with tartaric acid and sodium bicarbonate, then drying at elevated temperature. This allows the molecular water from the citric acid monohydrate to come out and bind the acids with the sodium bicarbonate. Wet granulation was tested by suspending citric acid monohydrate with sodium bicarbonate in ethanol and drying into a paste, then similarly dry ing the molecular water out of the citric acid monohydrate like for dry' granulation. For either dry or wet effervescent granules, the powders were passed through different sieve mesh sizes and then packed into the capsules. The reaction rates for capsules fabricated with these excipients were too slow (<50 kPa after 30 min in vitro in SIF).

[0209] Finally, another method tested was to put the mixed effervescent excipients in a polyvinyl pyrrolidone (PVP) matrix, which can dissolve upon aqueous liquid absorption in vitro. The PVP was dissolved in anhydrous ethanol and sodium bicarbonate and citric acid monohydrate were added, since ethanol does not initiate effervescent reaction, and a film was dried. The film was scraped off and ground with mortar and pestle and packed into the capsule (FIGS. 21A-21B). The amount of PVP added was varied to balance the reaction rate in vitro in SGF. as well as the ability to make a film that could be ground up and put into the capsule. The addition of PVP caused the excipients to take up more space inside the capsule.Example 6. Stabilization of Self-Pressurized Oral Capsules

[0210] Capsules were fabricated using UV-crosslinked gelatin capsules with a lacquer coating and containing a delivery orifice and effervescent excipients, and in some cases a drug compartment filled with powdered drug. The effervescent excipients were loaded into the bottom of the capsule body and the delivery orifice was created near the top. When included, the drug compartment was positioned adjacent to the delivery orifice and was filled with powdered drug. The capsule was designed to eject the drug out of the capsule upon failure of the delivery orifice due to elevated pressure in the capsule. This pressure elevation is caused by effervescent gas generation upon entry of water from surrounding intestinal fluid. However, the effervescent excipients are hygroscopic and pre-react, making long-term storage a challenge, and the current capsule design cannot delay release until after passage through the stomach.Enteric Coating to Prevent Drug Delivery in the Stomach

[0211] The self-pressurized capsules described herein are intended to deliver drug in the intestine, where the capsule is in close contact with the intestinal mucosa such that high- velocity drug ejection can penetrate the mucosal barriers. This approach is unlikely to work well in the stomach, where the capsule is not necessarily near the stomach wall, where effective drug ejection would need to occur. Design modifications to prevent drug ejection in the stomach were developed.

[0212] When placed in either SGF or SIF. capsule pressure increased over the course about 10 - 20 min and then burst (FIG. 22A). Capsule burst time in SGF was 17.3 ± 4.39 min and in SIF was 19.0 ± 7.75 min (FIG. 22D). Capsule burst time was not significantly different in SGF versus SIF because water can enter the capsule when in either fluid, and the effervescent excipients can start reacting as soon as they get wet. The burst pressure (FIG. 22B) and pressurization rate (FIG. 22C) of capsules in SGF and SIF were also not significantly different.

[0213] To prevent capsule burst in the stomach, it is possible to either (1) prevent water from entering the capsule from SGF, or (2) prevent the capsule from bursting when in SGF. Since preventing water uptake would be difficult, it is desirable to selectively coat the capsule with a material to strengthen the delivery orifice in SGF, but would disappear in SIF, so that the capsule could burst in the intestine.

[0214] Initially, an enteric coating was deposited on top of Tecoflex / Lacquer, which did not significantly prevent water absorption and selectively allowed for capsule burst only above acidic pH . Additionally, it was found that for all coatings, water likely enters by diffusion through the gelatin capsule wall, followed by a combination of osmosis and diffusion (FIGS. 23A-23C). Capsules containing lacquer coating only (no enteric coating) and only sodium bicarbonate were placed in SGF and did not have a pressure increase (FIG. 24). The minimal pressure increase is due to the temperature increase of the capsule being placed in 37 °C SGF.

[0215] A Eudragit enteric coating was also put on top of the exposed gelatin delivery orifice, and the Eudragit was found to prevent deflection of the delivery’ orifice as pressure built up in the capsule during in vitro testing in SGF. When the capsule was transferred to SIF. the Eudragit dissolved, and the delivery orifice burst. If the capsule with enteric coating was not moved from SGF to SIF, the pressure continued to increase without the delivery’ orifice bulging outwards (FIG. 25). For capsules left only in SGF, pressure reached greater than 200 kPa, but then failed at the Tecoflex coating or at the UV adhesive glue.

[0216] It was therefore determined that providing an enteric coating on the delivery orifice from the Eudragit family of methacrylic acid co-polymers, which are commonly used on hard gelatin capsules, would be effective for preventing premature drug release in the stomach. Eudragit L100-55 was chosen since it dissolves above pH 5.5, allowing for drug release in the upper to mid small intestine.

[0217] The enteric-covered capsule did not burst while in SGF for 30 min (FIG. 22A). After 30 min in SGF, capsules were immediately transferred to SIF to simulate passage from the stomach to the small intestine. Upon transfer to SIF. capsules burst in 11.9 ± 3.89 min (FIG. 2D), supporting the hypothesis that enteric-covered capsules could achieve selective and rapid drug delivery’ in the small intestine after passage through the stomach.

[0218] Burst time of enteric-covered capsules in SIF after pre-incubation in SGF was significantly faster than the burst time for non-covered capsules placed in SIF without pre- incubation in SGF (19.0 ± 7.75 min, Welch’s t-test, p = 0.0146). This indicates pre-incubationin SIF expedited capsule failure, probably due to already-elevated pressure in the capsule (due to pre-incubation in SGF) upon placement in SIF.

[0219] The capsule pressurization rate (until it plateaued) was similar for enteric-covered capsules compared to non-covered capsules (FIG. 22C), which suggests that the enteric covering did not affect the uptake of water from SGF, since water uptake kinetics should largely control pressure increase kinetics. Capsule burst pressure was approximately 2 - 3 times higher for entenc-covered capsules compared to non-covered capsules (FIG. 22B). This was likely because enteric-covered capsules had pressure build-up for 30 min in SGF before additional pressure build-up in SIF until they burst, allowing effervescent excipients to react for a longer time and achieve a higher pressure before burst.

[0220] Further understanding of how enteric covering prevents premature burst in the stomach comes from the appearance of the capsule delivery orifice in SGF and SIF. In SGF, the enteric covering is undissolved and covers the delivery orifice, while in SIF, the enteric covering dissolves and leaves the delivery orifice exposed. When in SGF, we found that the delivery orifice did not deflect outwards due to the mechanical strength of the enteric covering. In contrast, when in SIF (where the entenc covering dissolved off), the orifice bulged outward, eventually leading to its burst.Effect of Coating Thickness and Incubation Time on Delivery

[0221] The effect of varying the amount of enteric covering on burst pressure was also assessed to determine if capsules would still delay release while in the stomach. Capsules with different amounts of enteric covering were incubated in SGF for 30 min and then transferred to SIF (FIG. 26A). Burst pressure was significantly higher for capsules with enteric covering when compared to capsules without, but there was no significant difference in burst pressure among the capsules with different amounts of enteric covering.

[0222] Pressurization rate was also not significantly different among enteric-covered capsules, and was also not significantly different from non-covered capsules (FIG. 26A). To support the expectation that pressurization rate is related to water absorption rate, w ater uptake was directly measured in capsules with and without enteric covering. It was found that there was no significant difference (FIGS. 27A-27B). This indicates that absorption of water into the capsule was not affected by enteric covering.

[0223] Time to burst after transfer from SGF to SIF depended on the amount of enteric covering (FIG. 26A). Capsules with enteric covering had significantly longer time to burst compared to those without coating, and time to burst increased with increasing mass of enteric covering. The time to burst should depend on pressurization rate and dissolution rate of theenteric covering, since the deliver}' orifice cannot burst until the enteric covering dissolves in SIF. Since the pressurization rate did not increase with amount of enteric covering, it is believed that the longer time to burst associated with greater amounts of enteric covering can be explained by the increased time it takes to dissolve thicker enteric coverings, which delayed deliver}' orifice failure.

[0224] The effect of incubation time in SGF was also assessed to determine how gastric emptying time might affect capsule burst behavior. Enteric-covered capsules were kept in SGF for 0 min. (SIF only), 30 min (and then transferred to SIF), or infinite time (SGF only, until burst). The results demonstrated that burst pressure trended toward increased values (but without statistical significance), pressurization rate significantly decreased, and time to burst significantly increased with incubation in SGF (FIG. 26B). This indicates that gastric emptying time could affect capsule behavior.

[0225] Additionally, the time to burst for enteric-covered capsules upon transfer to SIF after 30-min SGF incubation w as not significantly different from the time to burst for enteric- covered capsules placed in SIF without pre-incubation in SGF (FIG. 26B). This indicates that the dissolution time of enteric covering in SIF was not affected by pre-incubation in SGF. This indicates that the mass of enteric covering could be used to control the time to burst in the small intestine, even with variability' in gastric emptying time.

[0226] These data can be better understood by closer examination of the capsules incubated in SGF indefinitely. The pressurization rate decreased with increasing time in SGF, which can be explained by examining the dependence of capsule pressure over time, where the pressurization rate was initially faster and then slowed down at later times (FIG. 28). In addition, the capsules incubated in SGF for infinite time did not burst at the orifice and the enteric covering did not dissolve, which is consistent with the capsule design. Instead, these capsules SGF failed at the connection between the pressure sensor and the capsule, which is an artifact of the measurement apparatus. Without that artifact, the capsule burst time in SGF would likely be longer.

[0227] To assess capsule pressurization behavior without the artifact caused by the pressure sensor connection, capsules were incubated in SGF indefinitely without a pressure sensor inserted and found that they failed after 61.4 ± 9.08 min (N = 3 replicates). The failure spot of these capsules was found in the body of the capsule and not at the delivery' orifice, which remained intact and covered by enteric covering. This suggests that non-uniformities in capsule body properties may provide points of weakness that can fail at very high pressures.Shelf-Life Stability of Self-Pressurized Capsules

[0228] A second barrier which prevents translation of the capsule is its short shelf-life stability. Stability for three days was used as an initial benchmark for establishing shelf-life stability to facilitate on-going studies.

[0229] Storage of capsules with the original design for three days at ambient temperature and humidity led to poor outcomes. Some of the capsules appeared to have undergone prereaction of effervescence, likely due to exposure to humidity, that built up so much internal pressure that the capsules exploded and broke the box in which they were contained. The residual excipients appeared clumpy and moist, unlike before storage.

[0230] The remaining capsules that had not exploded had cracks and holes in the surface, specifically at the parts of the capsule which were touching the excipients. When these capsules were incubated in SIF, they burst at locations other than the delivery orifice, such as at the cracks / holes in the capsule in the capsule wall. They had significantly lower burst pressure compared to fresh capsules (FIG. 29 A). The pressurization rate was also significantly lower after storage (FIG. 29B), further suggesting that the excipients had already reacted during storage. Time to burst (FIG. 29C) was similar before and after storage, and there was no lag time in pressure build-up upon placement in SIF.

[0231] Further analysis of these capsules by Karl Fischer measurement (FIG. 29D) showed that the excipients in capsules started with 8.68 ± 2.0 % w / w water and then gained 2.59 ± 0.27 % w / w water during storage, and the gelatin capsule walls started with 10.62 ± 0.97 % w / w water and then gained 2.58 ± 0.65 % w / w water (N = 8). Because the autocatalytic reaction between the excipients is initiated by water and generates more water, water generation by the effervescence reaction could have caused the gelatin and excipients to gain water.

[0232] Capsules without modifications were also stored for one w eek with desiccant in a sealed pouch at either room temperature or 4°C (FIG. 30A), then tested in vitro in SIF. Capsules failed (burst at locations other than the delivery orifice) and failures were large holes in the gelatin w all that could not be seen in the wall or coating before the in vitro test. For capsules stored at 4°C, there was some pressure increase before the failure and for those at room temperature, pressure did not increase. Capsules without modifications showed prereaction of effervescent excipients after 24 hours or less on the benchtop (FIG. 30B). indicating that the pre-reaction of effervescent excipients occurs in just a few hours.

[0233] After storage w ith desiccant or at cold temperatures to inhibit excipient prereaction, gelatin capsules became brittle and burst at the wrong location when submerged in SIF. Capsules stored at room temperature with or without desiccant had clumpy excipients, indicating pre-reaction. One capsule stored at room temperature without desiccant had so muchinternal pressure that built up during pre-reaction that the capsule burst in the storage container and shattered the capsule walls.

[0234] Capsules stored at cooler temperatures had less clumpy, pre-reacted excipients. However, storage at cool temperatures <15°C is not recommended for gelatin capsules and requiring storage on dry ice is not practical for clinical translation. Capsules stored at 4°C or with dry ice with or without desiccant often failed (the capsule burst prematurely at a location in the capsule wall besides the delivery orifice upon submersion in SIF in vitro).

[0235] FIGS. 31A-31B shows capsules stored with desiccant at 4°C had similar burst pressure to those stored at 4°C without desiccant. Capsules stored with desiccant had significantly greater time to burst, implying that reaction rate of the effervescent excipients was slower after storage with desiccant. Capsules stored at 4°C without desiccant had a 50% failure rate: 4 capsules failed, and 4 burst at the orifice (n = 8 total). Capsules stored at 4°C with desiccant had a lower failure rate: 1 capsule failed, and 5 burst at the orifice (n = 6 total). The addition of desiccant likely decreased the amount of water present in the capsule wall and excipients during storage. This decreased water likely prevented the pre-reaction of excipients (since effervescent reaction is an autocatalytic chain reaction any water initially present in the excipients or capsule wall can cause pre-reaction), resulting in slower reaction rate upon in vitro testing. By contrast, for capsules stored without desiccant, water present in the capsule or excipients could cause pre-reaction of excipients, which likely causes the internal pressure to build-up in the capsule during storage or affects the water content of the capsule walls. The elimination of moisture from the capsule wall could weaken the gelatin mechanical properties, which likely caused the high failure rate of the 4°C without desiccant group. Although the addition of desiccant helped reduce the failure rate, desiccating gelatin capsules can also cause capsule brittleness, since recommended gelatin hard capsule storage humidity’ is 35-65% RH.Increasing Self-Pressurized Capsule Shelf-Life

[0236] It was hypothesized that reducing capsule water content during storage could prevent effervescence pre-reaction. Water content was reduced during storage by two approaches: 1) pre-drying the citric acid (CA) by vacuum drying at elevated temperature and then storing with desiccant before assembly into the capsules, and 2) assembling capsules in a controlled-humidity glove box (RH = 15 - 19%). CA is known to be significantly more hygroscopic than SB, so removing the adsorbed water in CA should be more effective to reduce excipient reactivity.

[0237] Pre-Drying Citric Acid - Pre-drying citric acid mono hydrate prevented excipient pre-reaction, as it is a very hygroscopic excipient and the water initially present likely causesinitiation of the autocatalytic chain reaction with sodium bicarbonate. Citric acid monohydrate (theoretically has 8.57% w / w water) was dried in a 55 °C vacuum oven for 3 nights and lost 6.21 ±0.52% w / w water (n=6), and subsequently dried for 1 week in a desiccator and lost 7.50±0.71 % w / w water (n=6). The dried citric acid was mixed with fresh sodium bicarbonate.

[0238] The reduced reactivity7of the pre-dried excipients caused slow capsule pressurization rate in SIF (FIGS. 32A-32B). The capsules with the dried excipients had significantly lower burst pressure despite the same lacquer coatings, UV crosslinking time, and delivery orifice size. The reason for this is because the capsules with dried excipients took significantly longer time to burst (due to slow er reaction rate). The longer the exposed gelatin delivery7orifice on the capsule is submerged in aqueous solution, the more likely for thermal degradation, enzymatic degradation, and water absorption (FIGS. 33A-33B). A slower reaction rate means the capsule (and the exposed gelatin delivery orifice) are submerged in the aqueous solution for longer. There is a trade-off between the longer time the capsule is submerged in solution and the exposed delivery7orifice weakening in solution and bursting at low er pressures.

[0239] Additionally, after mixing the dried CA with sodium bicarbonate (SB) (having a water content of 3.32 ± 0.44% w / w water (N=4), fresh capsules tested in vitro for bursting behavior in SIF (FIG. 34A) show ed significantly lower burst pressure, lower pressurization rate, longer time to burst, and no lag time before bursting.

[0240] These data indicate that the reactivity of CA upon drying was significantly reduced. Low excipient reactivity is desirable for extending shelf-life storage, but is less desirable for drug delivery7, when high burst pressure is needed to penetrate mucosal barriers. The normalized burst pressure with dried CA in FIG. 34A corresponds to an absolute burst pressure of only 44.9 ± 21 kPa, which is 62% lower than capsules with non-dried CA (118.5 ± 45 kPa). The burst pressure with dried CA would not be high enough to penetrate intestinal mucosa.

[0241] Tecoflex Coating - It appears that the bursting behavior w as influenced by both the amount of residual w ater in the capsules as well as the w ater that enters capsules from SIF. Since water content in the capsule was reduced (to provide stability during storage), the rate of ater entry into capsules from SIF was increased (to more-rapidly increase water content for drug delivery ). Tecoflex was identified as an alternate hydrophobic coating instead of the lacquer used in the original capsule design that would allow more w ater uptake across the capsule w all, but still remain rigid and prevent dissolution of the gelatin. Tecoflex is an aliphatic polyether-based thermoplastic polyurethane that is used in many invasive medical products, is expected to be strong due to its value on the Shore durometer hardness scale, andis expected to have greater water permeability because of the presence of many soft copolymer segments.

[0242] Tecoflex coated capsules absorbed significantly more water (FIGS. 33A-33B) as compared to lacquer coated capsules, allowing for faster water uptake to initiate effervescence in the capsule. Therefore, as expected, replacing lacquer with Tecoflex enabled capsules to gain more water when placed in SIF or SGF (FIGS. 34B-34C, 35A-35B). The Tecoflex coating was only applied to the bottom of the capsule body, adjacent to the excipients, and lacquer was applied to the rest of the capsule body and top. Tecoflex-based capsules with dried CA did not show improvement compared to lacquer-based capsulate, exhibiting similar burst pressure and pressurization rate (FIG. 34D). However, when evaluating enteric-covered capsules with dried CA (which is the main interest for drug delivery), Tecoflex allowed for significantly higher burst pressure and pressurization rate than without Tecoflex, so this design was further pursued (FIG. 34E).

[0243] To better understand water uptake by capsules, the effect of water transport was by osmosis in addition to diffusion was studied (FIGS. 35A-35C). By preparing capsules containing no CA or SB excipients, the driving force for water uptake by osmosis was removed due to the high (i.e., saturated) concentration of excipients that would be present inside the capsule. It was found that water uptake in capsules containing excipients was significantly greater than in capsules without excipients when using capsules with Tecoflex but not when using capsules without Tecoflex. In this study, dried CA and sodium citrate dihydrate were used as non-effervescent excipients (at the same concentration as the dried CA and SB used in the usual capsules) to provide an osmotic driving force without the added effects of effervescence. Altogether, these data indicate that the osmotic driving force plays a significant role in water uptake in capsules with Tecoflex. This finding could explain the higher burst pressure and pressurization rate for these capsules seen in FIG. 34E.

[0244] Based on positive results with dried CA in capsules with Tecoflex, behavior in SIF and SGF was further examined. Similar to regular capsules, the capsules with Tecoflex needed enteric covering to delay release while in SGF (FIG. 36A). Burst pressure (FIG. 36B) and pressurization rate (FIG. 36C) were also significantly higher with enteric-covered capsules than non-enteric covered capsules with Tecoflex, likely because both Tecoflex (FIGS. 35A- 35C) and enteric covering (FIG. 27B) allowed capsules to absorb more water.

[0245] By reducing water content in dried CA and maintaining high-pressure burst behavior by using a Tecoflex coating, it was hypothesized that these modified capsules would be able to retain drug delivery performance even after storage. The improved capsules withenteric and Tecoflex coating (and prepared in a low humidity chamber) had similar burst pressures before and after multi-day storage (FIGS. 37A-37B). Time to burst was longer after storage than before. Enteric coating (since capsules were tested in SGF for 30 min then SIF) helped to prevent the delivery orifice from prematurely bursting despite the longer time to burst.

[0246] After storage for 3 days, none of the modified capsules exploded during storage or had visible cracks in the gelatin. However, capsules still had small holes visible in the gelatin and 60% (3 / 5) of capsules burst at these holes instead of the delivery orifice when tested in SIF (FIG. 38A). Burst pressure and pressurization rate (FIG. 38B) were also significantly lower than fresh capsules, implying that the excipients had already reacted during storage. There was no lag time in pressure increase after storage, and time to burst was not significantly different between fresh and stored capsules (FIG. 38C).

[0247] Fabrication and Storage at Reduced Humidity’ - Since pre-drying CA was insufficient to prevent premature excipient pre-reaction during storage, it was hypothesized that the water content of the air trapped inside the capsule should be reduced. Capsules with Tecoflex and dried CA were therefore prepared in a controlled-humidity glove box (15-19 %RH) and then stored at 15-19 %RH to reduce the amount of water that could be absorbed by the CA from the air. Humidity' was not reduced further because gelatin capsules become brittle at lower humidity levels.

[0248] After fabrication and storage in this way, non-covered capsules placed in SIF did not have any visible holes or cracks in the gelatin, and effervescent excipients did not look wet or clumpy. All the capsules burst at the delivery' orifice and burst pressure and pressurization rates were not significantly different after 3 days compared to freshly made capsules (FIG.39A). There was also a lag time before pressure release for the stored capsules of 8.48±1.37 min. This indicated that there was initially7insufficient water in the capsule for the effervescence reaction, such that it took time for water from SIF to cross the capsule wall and come in contact with the excipients. Total time to burst was not significantly different (FIG. 39A) between fresh and stored capsules.

[0249] Karl Fischer titration showed that the excipients did not gain a significant amount of water during storage (FIG. 39B), indicating improved stability7over non-dried excipients without controlled-humidity fabrication and storage (FIG. 29D). Gelatin in the capsule wall significantly lost water during storage (FIG. 39B), which could be due water loss from the gelatin to the surrounding low-humidity air (15 - 19 %RH), which was less humid than the recommended hard gelatin capsule storage condition (35 - 65 %RH).

[0250] Enteric-covered capsules were next tested with Tecoflex, dried CA, and controlled humidity after storage and placement in SGF followed by SIF. Burst pressure, pressurization rate, and time to burst were all similar to before storage (FIG. 39C), and all capsules burst at the delivery orifice only after being transferred to SIF after 30 min in SGF. All but one sample (75%) had essentially no lag time before pressure increase. Altogether, these data indicate that enteric covering did not affect capsule stability performance.

[0251] As a control experiment, capsules were stored with non-dried CA but prepared in the controlled humidity glove box to determine the sole effect of controlled humidity on capsule storage stability (FIG. 39D). After storage, these control capsules had similar burst pressure, but significantly lower pressurization rate and longer time to burst. All capsules burst at the delivery orifice and did not exhibit a lag time after storage. The lower pressurization rate and longer time to burst shows that these control capsules were not fully stable, indicating that both drying CA and using a controlled humidity environment are necessary for maintaining capsule performance after storage.30 Dav Storage Stability

[0252] To assess storage stability beyond 3 days, capsule bursting behavior was measured for up to 30 days. After extended storage, capsules burst through the delivery orifice and did not have visible holes in the gelatin even after storage of up to 30 days. However, beyond 3 days storage, burst pressure (FIG. 40 A) and pressurization rate (FIG. 40B) were significantly lower, indicating a loss of capsule stability. The time to burst significantly increased (FIG. 40C), and lag time for 15- and 30-day storage was significantly longer than for 3 days (FIG. 40C).

[0253] The pressurization rate was calculated as the average over the full incubation time in SIF (i.e.. including the lag time, during which there was very little pressure increase). If the initial lag phase is subtracted, then the time in SIF until capsule burst did not differ between fresh and stored capsules and the pressurization rate after the lag time also did not depend on storage time. This indicates that capsule storage primarily affected capsules by delaying onset of pressure rise rather than slowing pressurization rate.

[0254] The increased time until burst time after extended storage prolonged exposure of the gelatin delivery orifice in SIF. This may have reduced burst pressure due to increased gelatin degradation by SIF, causing the capsule to burst at a lower pressure. Altogether, it was hypothesized that the prolonged incubation time in SIF due to an increased lag time led to a weakening of the delivery orifice, leading to a lower burst pressure after 15 days or longer.Alternative Methods to Improve Shelf-Life Stability

[0255] Other approaches besides drying CA and using a controlled-humidity chamber to reduce effervescence reactivity’ during storage were also investigated. Instead of using a controlled-humidity chamber for capsule assembly, desiccant was added to the capsule storage container to reduce water content of the surrounding air during storage. However, 17% of capsules failed after 24 h storage, despite the presence of desiccant (FIG. 41A). By visual observation, capsules also appeared more brittle after storage. The capsules which failed burst at various locations other than the delivery’ orifice, such as at holes or cracks in the gelatin capsule yvall that appeared after storage.

[0256] Since desiccant yvas not sufficient for preventing effervescence pre-reaction, capsules were also stored at lower temperature (at 4°C or with dry ice) to reduce reactivity of the excipients. Hoyvever. cold storage resulted in brittle gelatin that had high failure rates (>20%) and burst at locations other than the delivery orifice (FIG. 41 A). Since hard gelatin capsules are recommended to be stored at 15 - 25°C and 35 - 65 %RH, the addition of desiccant or lower temperature likely compromised the mechanical integrity of the gelatin capsule walls.

[0257] Using a less hygroscopic acid source instead of CA was also tested, such as fumaric acid, but pressurization rate was too sloyv (FIG. 41B). Extrapolating from data collected for almost 1 h, reaching a desired burst pressure of >100 kPa would have taken more than 5 h. Performing wet or dry granulation of the effervescent excipients (commonly used for effervescent tablets) was also briefly tested, but pressure increase was also too sloyv after these processing steps. Effervescent excipients were also coated in a thin layer of dissolvable polymer (0.13 % w / w PVP in ethanol) that could dissolve off in water (e.g., in SIF) but acted as a barrier between the SB and CA during storage. Hoyvever, pressure increase yvas very’ slow (FIG. 41C), probably because not enough water entered the capsule from SIF to sufficiently dissolve the PVP, so this method yvas not pursued further.

[0258] Instead of a dissolution-triggered barrier between the SB and CA, a thermally- triggered barrier was also made using lipids (Witepsol S55) that were solid at room temperature and only melted above 33 C. Although the lipid formulation melted when the capsule yvas placed in SIF at 37 °C, the melted lipid appeared to still block the SB and CA from having sufficient contact to generate a noticeable pressure increase.EMBODIMENTS

[0259] Some embodiments of the present disclosure can be described in view of one or more of the following:

[0260] Embodiment 1. A dosage form for administration of a drug to a patient, the dosage form comprising: a capsule comprising a capsule wall defining an interior space; drug particles disposed within a first portion of the interior space adjacent a pre-defined area of weakness in the capsule; and an excipient composition located within the interior space, wherein the excipient composition is configured to react, or to phase change, and produce a gas which pressurizes the interior space, and wherein the pre-defined area of weakness in the capsule is configured to rupture under the pressurization by the gas. forming a release aperture through the capsule (capsule wall and / or a coating thereon) through which the drug particles are ejected together with the gas.

[0261] Embodiment 2. The dosage form of embodiment 1, wherein at least part of the capsule wall is configured to permit water to diffuse therethrough and contact the excipient composition to produce the gas.

[0262] Embodiment 3. The dosage form of embodiment lor 2, wherein the capsule is configured for oral administration to the patient, such as a human patient.

[0263] Embodiment 4. The dosage form of any one of embodiments 1 to 3, wherein the drug particles comprise a biologic.

[0264] Embodiment 5. The dosage form of any one of embodiments 1 to 4, wherein the excipient composition is configured to undergo a reaction with water to produce a gas, such as CO2 gas.

[0265] Embodiment 6. The dosage form of any one of embodiments 1 to 5, wherein the excipient composition comprises an effervescent powder, including an acid component and a base component.

[0266] Embodiment 7. The dosage form of embodiment 6, wherein the acid component comprises citric acid, tartaric acid, fumaric acid, ascorbic acid, acetic acid, malic acid, lactic acid, phosphoric acid, or a combination thereof.

[0267] Embodiment 8. The dosage form of embodiment 6 or 7, wherein the base component comprises sodium bicarbonate, sodium phosphate, calcium carbonate, magnesium carbonate, potassium bicarbonate, or a combination thereof.

[0268] Embodiment 9. The dosage form of any one of embodiments 6 to 8, wherein the effervescent powder comprises citric acid (e.g., citric acid monohydrate) and sodium bicarbonate.

[0269] Embodiment 10. The dosage form of any one of embodiments 1 to 9, wherein the release aperture has a diameter between 0. 1 mm and 10 mm, preferably between 0.5 mm and 2 mm.

[0270] Embodiment 11. The dosage form of any one of embodiments 1 to 10, which is configured to pressurize the interior space to a pressure from 30 kPa to 300 kPa, preferably from 100 kPa to 170 kPa, before the rupture of the pre-defined area of weakness.

[0271] Embodiment 12. The dosage form of any one of embodiments 1 to 11, wherein the interior space further comprises a funnel structure which tapers toward the pre-defined area of weakness and is configured to direct the gas and drug particles through the release aperture in the capsule wall.

[0272] Embodiment 13. The dosage form of embodiment 12, wherein the drug particles are disposed within the opening of the funnel structure.

[0273] Embodiment 14. The dosage form of any one of embodiments 1 to 13, wherein the capsule wall comprises a pair of rounded ends and an elongated cylindrical sidewall therebetween.

[0274] Embodiment 15. The dosage form of embodiment 14, wherein the pre-defined area of weakness and the release orifice are located in the elongated cylindrical sidewall.

[0275] Embodiment 16. The dosage form of any one of embodiments 1 to 15, wherein the capsule comprises one or more bioerodible materials.

[0276] Embodiment 17. The dosage form of any one of embodiments 1 to 16, wherein the capsule wall comprises a cross-linked, biocompatible polymer.

[0277] Embodiment 18. The dosage form of any one of embodiments 1 to 17, wherein the capsule wall comprises gelatin.

[0278] Embodiment 19. The dosage form of any one of embodiments 1 to 18, wherein the capsule wall comprises one or more coatings.

[0279] Embodiment 20. The dosage form of embodiment 19, wherein at least one of the one or more coatings is over a hole in the capsule wall, wherein an area of coating over the hole serves as the predefined area of weakness.

[0280] Embodiment 21. The dosage form of embodiment 19 or 20, wherein at least one of the one or more coatings covers the entire capsule except for the pre-defined area of weakness.

[0281] Embodiment 22. The dosage form of any one of embodiments 19 to 21, wherein at least one of the one or more coatings is an enteric coating.

[0282] Embodiment 23. The dosage form of any one of embodiments 1 to 22, wherein the interior space further comprises a wicking structure to convey water from an interior surface of the capsule wall to the excipient composition.

[0283] Embodiment 24. The dosage form of any one of embodiments 1 to 23, wherein the excipient composition is in a dry powder form.

[0284] Embodiment 25. The dosage form of any one of embodiments 1 to 24, wherein the excipient composition further comprises a non-reactive material configured to slow or delay the reaction or phase change, optionally wherein the nonreactive material is configured to slow or delay the reaction of the excipient composition with the water.

[0285] Embodiment 26. The dosage form of embodiments 25, wherein the non-reactive material serves as a temporary physical barrier between two or more reactive components of the excipient composition.

[0286] Embodiment 27. The dosage form of embodiments 25 or 26, wherein the nonreactive material comprises polyethylene glycol (PEG), mannitol, microcrystalline cellulose, polyvinylpyrrolidone (PVP), tartaric acid, or a combination thereof.

[0287] Embodiment 28. The dosage form of any one of embodiments 25 to 27, wherein the non-reactive material has a melting temperature of 37 °C or greater.

[0288] Embodiment 29. The dosage form of any one of embodiments 25 to 28, wherein the non-reactive material comprises a Witepsol™ wax or other glycerol esters of saturated fatty acids.

[0289] Embodiment 30. The dosage form of any one of embodiments 1 to 29, wherein the excipient composition is disposed within a second region of the interior space, separate from the first region, preferably wherein a filter membrane is disposed between the first and second regions of the interior space.

[0290] Embodiment 31. The dosage form of embodiment 30, wherein the filter membrane is positioned at (e g., on, in, over, adjacent) an opening of the funnel structure within the first interior space.

[0291] Embodiment 32. The dosage form of any one of embodiments 1 to 31. wherein the drug particles have a size from 10 nm to 1000 pm.

[0292] Embodiment 33. The dosage form of any one of embodiments 1 to 32, which is configured to eject the drug particles within a gastrointestinal tract of the patient.

[0293] Embodiment 34. The dosage form of embodiments 33, wherein the dosage form is configured to eject the gas and drug particles with a velocity’ effective to displace at least part of a mucosal barrier, and / or to drive the drug particles across at least part of a mucosal barrier, of an intestine within the gastrointestinal tract.

[0294] Embodiment 35. The dosage form of embodiments 33 or 34, which is configured to eject the drug particles after a period from 10 minutes to 4 hours following oral administration to the patient.

[0295] Embodiment 36. The dosage form of embodiments 33 or 34, which is configured to eject the drug particles when the dosage form is within the small intestine or colon of the patient.

[0296] Embodiment 37. The dosage form of any one of embodiments 1 to 36, which is configured for gastrointestinal, buccal, sublingual, nasal, vaginal, rectal, or ocular administration.

[0297] Embodiment 38. A method of administering a drug to a patient, the method comprising: administering the dosage form of any one of embodiments 1 to 37 into the patient; and then ejecting the drug particles from the capsule toward a mucosal barrier within the patient upon generation of a pressure within the dosage form sufficient to rupture the predefined area of weakness in the capsule of the dosage form.

[0298] Embodiment 39. The method of embodiment 38, wherein the particles of the drug are ejected following a predetermined period after the administering of the dosage form.

[0299] Embodiment 40. The method of embodiment 38 or 39, wherein the administering is by oral delivery and the particles of the drug are ejected toward the mucosal barrier of the gastrointestinal tract of the patient, optionally following the dosage form reaching a position within the gastrointestinal tract having a preselected pH.

[0300] Modifications and variations of the methods and devices described herein w ill be obvious to those skilled in the art from the foregoing detailed description. Such modifications and variations are intended to come within the scope of the appended claims.

Claims

CLAIMSThat which is claimed is:

1. A dosage form for administration of a drug to a patient, the dosage form comprising: a capsule comprising a capsule wall defining an interior space; drug particles disposed within a first portion of the interior space adjacent a predefined area of weakness in the capsule; and an excipient composition located within the interior space, wherein the excipient composition is configured to react, or to phase change, and produce a gas which pressurizes the interior space, and wherein the pre-defined area of weakness in the capsule is configured to rupture under the pressurization by the gas, forming a release aperture through the capsule through which the drug particles are ejected together with the gas.

2. The dosage form of claim 1, wherein at least part of the capsule wall is configured to permit water to diffuse therethrough and contact the excipient composition to produce the gas.

3. The dosage form of claim 1, wherein the capsule is configured for oral administration to the patient, such as a human patient.

4. The dosage form of claim 1, wherein the drug particles comprise a biologic.

5. The dosage form of claim 1, wherein the excipient composition is configured to undergo a reaction with water to produce a gas, such as CO2 gas.

6. The dosage form of claim 5, wherein the excipient composition comprises an effervescent powder, including an acid component and a base component.

7. The dosage form of claim 6, wherein the acid component comprises citric acid, tartaric acid, fumaric acid, ascorbic acid, acetic acid, malic acid, lactic acid, phosphoric acid, or a combination thereof.

8. The dosage form of claim 6, wherein the base component comprises sodium bicarbonate, sodium phosphate, calcium carbonate, magnesium carbonate, potassium bicarbonate, or a combination thereof.

9. The dosage form of claim 6, wherein the effervescent powder comprises citric acid and sodium bicarbonate.

10. The dosage form of claim 1, wherein the release aperture has a diameter between 0. 1 mm and 10 mm, preferably between 0.5 mm and 2 mm.

11. The dosage form of claim 1, which is configured to pressurize the interior space to a pressure from 30 kPa to 300 kPa, preferably from 100 kPa to 170 kPa, before the rupture of the pre-defined area of weakness.

12. The dosage form of claim 1, wherein the interior space further comprises a funnel structure which tapers toward the pre-defined area of weakness and is configured to direct the gas and drug particles through the release aperture in the capsule wall.

13. The dosage form of claim 12, wherein the drug particles are disposed within the opening of the funnel structure.

14. The dosage form of claim 1, wherein the capsule wall comprises a pair of rounded ends and an elongated cylindrical sidewall therebetween.

15. The dosage form of claim 14, wherein the pre-defined area of weakness and the release orifice are located in the elongated cylindrical sidewall.

16. The dosage form of claim 1, wherein the capsule comprises one or more bioerodible materials.

17. The dosage form of claim 1, wherein the capsule wall comprises a cross-linked, biocompatible polymer.

18. The dosage form of claim 1, wherein the capsule wall comprises gelatin.

19. The dosage form of claim 1, wherein the capsule wall comprises one or more coatings.

20. The dosage form of claim 19, wherein at least one of the one or more coatings is over a hole in the capsule wall, wherein an area of coating over the hole serves as the predefined area of weakness.

21. The dosage form of claim 19, wherein at least one of the one or more coatings covers the entire capsule except for the pre-defined area of weakness.

22. The dosage form of claim 19, wherein at least one of the one or more coatings is an enteric coating.

23. The dosage form of claim 1, wherein the interior space further comprises a wi eking structure to convey water from an interior surface of the capsule wall to the excipient composition.

24. The dosage form of claim 1, wherein the excipient composition is in a dry powder form.

25. The dosage form of claim 1, wherein the excipient composition further comprises a non-reactive material configured to slow or delay the reaction or phase change, optionally wherein the nonreactive material is configured to slow or delay the reaction of the excipient composition with the water.

26. The dosage form of claim 25, wherein the non-reactive material serves as a temporary physical barrier between reactive components of the excipient composition.

27. The dosage form of claim 25, wherein the non-reactive material comprises polyethylene glycol (PEG), mannitol, microcrystalline cellulose, polyvinylpyrrolidone (PVP), tartaric acid, or a combination thereof.

28. The dosage form of claim 25, wherein the non-reactive material has a melting temperature of 37 °C or greater.

29. The dosage form of claims 25, wherein the non-reactive material comprises a Witepsol™ wax or other glycerol esters of saturated fatty acids.

30. The dosage form of claim 1, wherein the excipient composition is disposed within a second region of the interior space, separate from the first region, preferably wherein a filter membrane is disposed between the first and second regions of the interior space.

31. The dosage form of claim 30, wherein the filter membrane is positioned on an opening of the funnel structure within the first interior space.

32. The dosage form of claim 1, wherein the drug particles have a size from 10 nm to 1000 pm.

33. The dosage form of claim 1, which is configured to eject the drug particles within a gastrointestinal tract of the patient.

34. The dosage form of claim 33, wherein the dosage form is configured to eject the gas and drug particles with a velocity effective to displace at least part of a mucosal barrier, and / or to drive the drug particles across at least part of a mucosal barrier, of an intestine within the gastrointestinal tract.

35. The dosage form of claim 33, which is configured to eject the drug particles after a period from 10 minutes to 4 hours following oral administration to the patient.

36. The dosage form of claim 33, which is configured to eject the drug particles when the dosage form is within the small intestine or colon of the patient.

37. The dosage form of claim 1, which is configured for gastrointestinal, buccal, sublingual, nasal, vaginal, rectal, or ocular administration.

38. A method of administering a drug to a patient, the method comprising: administering the dosage form of any one of claims 1 to 37 into the patient; and then ejecting the drug particles from the capsule toward a mucosal barrier within the patient upon generation of a pressure within the dosage form sufficient to rupture the pre-defined area of weakness in the capsule of the dosage form.

39. The method of claim 38, wherein the particles of the drug are ejected following a predetermined period after the administering of the dosage form.

40. The method of claim 38. wherein the administering is by oral delivery and the particles of the drug are ejected toward the mucosal barrier of the gastrointestinal tract of the patient, optionally following the dosage form reaching a position within the gastrointestinal tract having a preselected pH.

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